AU2005217199A1 - Tetrahydroquinolinones and their use as antagonists of metabotropic glutamate receptors - Google Patents

Tetrahydroquinolinones and their use as antagonists of metabotropic glutamate receptors Download PDF

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AU2005217199A1
AU2005217199A1 AU2005217199A AU2005217199A AU2005217199A1 AU 2005217199 A1 AU2005217199 A1 AU 2005217199A1 AU 2005217199 A AU2005217199 A AU 2005217199A AU 2005217199 A AU2005217199 A AU 2005217199A AU 2005217199 A1 AU2005217199 A1 AU 2005217199A1
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Prior art keywords
quinolin
dihydro
dimethyl
alkyl
phenyl
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AU2005217199A
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AU2005217199B2 (en
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Wojciech Danysz
Markus Henrich
Ieva Jaunzeme
Aigars Jirgensons
Ivars Kalvinsh
Valerjans Kauss
Christopher Graham Raphael Parsons
Maksims Vanejevs
Tanja Weil
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Merz Pharma GmbH and Co KGaA
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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WO 2005/082856 PCT/GB2005/000717 TETRAHYDROQUINOLINONES AND THEIR USE AS ANTAGONISTS OF METABOTROPIC GLUTAMATE RECEPTORS FIELD OF THE INVENTION 5 [0001] The present invention is concerned with novel metabotropic glutamate receptor (mGluR) antagonists, methods for their synthesis and the treatment and/or prevention of neurological disorders. BACKGROUND~OF THE INVENTION 10 [0002] Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of a neurotransmitter released by a neuron, which neurotransmitter has a specific effect on a neuroreceptor of another neuron. [0003] L-glutamic acid is considered to be the major excitatory 15 -neurotransmitter in the mammalian CNS, consequently playing a critical role in a large number of physiological processes. Glutamate-dependent stimulus receptors are divided into two main groups. The first group comprises ligand controlled ion channels whereas the second comprises metabotropic glutamate receptors (mGluR). Metabotropic glutamate receptors are a 20 subfamily of G-protein-coupled receptors (GPCR). [0004] At present, eight different members of these mGluRs are known. On the basis of structural parameters such as sequence homology, the second messenger system utilized by these receptors and their different affinity to 25 low-molecular weight compounds, these eight receptors can be divided into three groups: mGluR1 and mGluR5 belong to group I which couple to phospholipase C and their activation leads to intracellular calcium-ion mobilization. Both mGluR2 and mGluR3 belong to group 11 and mGluR4, mGluR6, mGIuR7 and mGluR8 belong to group Ill, which couple to adenyl 30 cyclase with their activation causing a reduction in second messenger cAMP and as such a dampening of the neuronal activity. [0005] The presence of Group I mGluR antagonists has been shown to result in a reduced presynaptic release of the neurotransmitter glutamate 1 WO 2005/082856 PCT/GB2005/000717 and consequently, to decrease glutamate-mediated neuronal excitation via postsynaptic mechanisms. Since a variety of pathophysiological processes and disease states affecting the CNS are thought to be due to excessive glutamate induced excitation, group I mGluR antagonists could be 5 therapeutically beneficial in the treatment of CNS diseases. [0006] Therefore, group I mGluR antagonists may be administered to provide neuroprotection in acute and chronic pathological conditions such as: AIDS-related dementia, Alzheimer's disease, Creutzfeld-Jakob's 10 syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving B-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), 15 olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, vascular and frontal lobe dementia, eye injuries, eye disorders (e.g. glaucoma, retinopathy), head and spinal cord injuries / trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), seizures/ 20 convulsions / epilepsy, glioma and other tumours, inner ear insult (e.g. in tinnitus, sound or drug-induced), L-dopa-induced and tardive dyskinesias, Wilson's disease. [0007] Other indications in this context include a symptomatological effect on 25 the following conditions: addiction (nicotine, alcohol, opiate, cocaine, amphetamine obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome and hyperactive children, autism, seizures / convulsions / epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff 30 syndrome, vascular dementia, HIV infections, Down's syndrome), depression (including that resulting from Boma virus infection) and bipolar manic-depressive disorder, drug tolerance e.g. to opioids, dyskinesia (e.g. L Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, 2 WO 2005/082856 PCT/GB2005/000717 multiple sclerosis, muscle spasms, pain (chronic and acute), Parkinson's disease, post traumatic stress disorder, schizophrenia, spasticity, tinnitus, Tourette's syndrome, urinary incontinence and vomiting, Wilson's disease. 5 THE PRESENT INVENTION [0008] We have determined that certain tetrahydroquinolones are Group I mGluR antagonists. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve excessive glutamate induced excitation of the CNS. These substances are preferably 10 administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients. [0009] Tetrahydroquinolinones have been disclosed in the art. For example, 15 Kajigaeshi, Shoji; Shirakawa, Shinsuke; Nishida, Akiko; Noguchi, Michihiko, Chemistry Express (1991), 6(7), 527-30 (CODEN: CHEXEU ISSN:0911 9566. CAN 115:135894 AN 1991:535894 CAPLUS) disclose 2 Benzylsulfanyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile. However, this compound is not demonstrated to have activity as a Group I 20 mGluR antagonist. 2-Benzylsulfanyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile; 2-(2-Methoxyphenyl)-7,8-dihydro-6H-quinolin-5-one; 2 Benzyloxy-7,8-dihydro-6H-quinolin-5-one; 3-Nitro-7,8-dihydro-6H-quinolin-5 one were disclosed by: John Wyeth and Brother Ltd., UK (WO 9521825); ICI Australia Ltd., Australia; Australian Institute of Marine Science (WO 25 8802251); Karo Bio AB, Swed. (WO 2004037792); Hoechst-Roussel Pharmaceuticals Inc., USA (EP 489379); Warner-Lambert Company, USA (WO 9834921); The Hong Kong University of Science and Technology, Hong Kong (US 6472408); Dotsenko, V. V. et al. East-Ukrainian National University, Luhansk, Ukraine, Russian Chemical Bulletin(2002), 51(8), 1556 30 1561; Molina, Pedro et al. Fac. Quim., Univ. Murcia, Murcia, Spain, Tetrahedron (1995), 51(4), 1265-76; Ruda, Marcus C et al. Karo Bio AB, Swed., Heterocyclic Communications (2003), 9(6), 571-574; Carlier, Paul R et al. Hong Kong University of Science and Technology, Kowloon, Hong Kong, Angewandte Chemie, International Edition (2000), 39(10), 1775-1777; 3 WO 2005/082856 PCT/GB2005/000717 Fink, David M et al. Hoechst-Roussel Pharmaceuticals Inc., Somerville, USA, Journal of Medicinal Chemistry (1995), 38(18), 3645-51; Marcoux, Jean-Francois et al. Merck & Co., Rahway, NJ, USA, Journal of Organic Chemistry (2001), 66(12), 4194-4199; Hoffman, Jacob M et al. Merck Sharp 5 and Dohme Res. Lab., West Point, USA, Journal of Organic Chemistry (1984), 49(1), 193-5. No metabotropic activity has been demonstrated for these compounds. OBJECTS OF THE INVENTION 10 [0010] It is an object of the present invention to provide novel pharmaceutical compounds which are tetrahydroquinolone Group I mGluR antagonists and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating undesirable CNS disorders which involve excessive glutamate 15 induced excitation of the CNS by employing a compound of the invention or a pharmaceutical composition containing the same. An additional object of the invention is the provision of a process for producing the tetrahydroquinolone active principles. Yet additional objects will become apparent hereinafter, and still further objects will be apparent to one skilled 20 in the art. SUMMARY OF THE INVENTION [0011] What we therefore believe to be comprised by our invention may be summarized inter alia in the following words: 25 Compounds of Formula IA R4 O
R
5 R R' R IA R2 N R 8 30
R
1 0
R
9 wherein
R
2 represents C 2
-
6 alkyl, cycloC 3
-
12 alkyl, cycloC 3
-
12 alkyl-C1.
6 alkyl, 4 WO 2005/082856 PCT/GB2005/000717
C
2 .salkenyl, C 2
-
6 alkynyl, aryl, biaryl, aryl-heteroaryl, heteroaryl heteroaryl, heteroaryl-ary), aryl-CI.
6 alkyl, aryl-C 2 -6alkenyl, aryl
C
2
-
6 alkynyl, heteroaryl, heteroaryl-C 1
.
6 alkyl, heteroary-C 2
-
6 alkenyl, heteroaryl-C 2
.
6 alkynyl, 2,3-dihydro-1 H-indenyl, C 2 -ealkoxy, hydroxy 5 C 2
-
6 alkoxy, cycloC3-1 2 alkoxy, cycloC 3
-
1 2 alkyl-C1.ealkoxy, aryloxy, aryl
C
1
-
6 alkoxy, C 1
.
6 alkoxy-C 1
.
6 alkyl, C 1
.
6 alkylthio, C 4
.
6 alkenylthio, cycloC 3
-
1 2 alkylthio, cycloC 3 -1 2 alkyl-C1.
6 alkylthio, cycloC 3
..
12 alkyl
C
3 .ealkenylthio, C 1
.
6 alkoxy-C 1
.
6 alkylthio, C1.ealkoxy-C 3 .ealkenylthio, aryl-C 3
.
6 alkenylthio, heteroaryl-C 1
.
6 alkylthio, C 1
.
6 alkylsulfonyl, 10 cycloC 3 -1 2 alkyl-C1.
6 alkylsulfonyl, aryl-C 1
.
6 alkylsulfonyl,
C
1
.
6 alkylamino, di-C 1 ..alkylamino, CycIOC 3 -1 2 alkylamino, C 1
.
6 alkoxy cycloC 3 -1 2 alkylamino, cycloC 3
-
12 alkyl-C1.
6 alkylamino, di-C 1
.
6 alkylamino-C 1
.
6 alkyl, C1.
6 alkoxy-C 2
-
6 alkylamino, arylamino, aryl
C
1 .ealkylamino, N-cycloC 3 -1 2 alkyl-N-C 1
.
6 alkylamino, N-aryl-N 15 C 1
.
6 alkylamino, N-arylC1.
6 alkyl-N-C1..
6 alkylamino, 2-indanylamino, 1,2,3,4-tetrahydroisoquinolin-2-yl, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C 1
..
6 alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yI, 20 heteroaryl-C1.
6 alkoxy, heteroarylamino, heteroaryl-C 1
.
6 alkylamino, -NHC(=O)-R", -NHSO 2 -R, -NHC(=O)OR, -C(=O)NH-R", or
-C
1
.
6 alkyl-C(=0)NH-R", wherein the cycloC 3
-
12 alkyl is optionally unsaturated and wherein one carbon atom in the cycloC3-12alkyl moiety may be replaced by an oxygen atom or an NR 1 2 -moiety; 25
R
3 represents hydrogen, cyano, nitro, halogen, C 1
.
6 alkyl, CF 3 , heteroaryl, 2,3-dihydro-1H-indenyl, hydroxy, C 1
.
6 alkoxy, pyrrolidino, piperidino, or morpholino; 30 R 4 represents hydrogen, halogen, nitro, C 1 ..alkoxy, or hydroxy
C
2
-
6 alkoxy;
R
5 and R, which may be the same or different, each independently represent hydrogen, hydroxy, Ci.
6 alkyl; cycIoC 3 -1 2 alkyl, C 2
-
6 alkenyl, 5 WO 2005/082856 PCT/GB2005/000717
C
1 .ealkoxy, C1.
6 alkoxy-C1.
6 alkyl, C1.6alkylthio, C 3
.
6 alkenylthio, C1-6 alkylamino, di-C 1 .ealkylamino, cycloC 3
-
12 alkylamino, di-C1. alkylamino
C
1
.
6 alkyl, aryl-C 1
.
6 alkylamino, aryl, aryl-C 1 .ealkyl, or aryl-C 2
-
6 alkenyl; 5 or one of R and R 6 and one of R 7 and R 8 together represent -(CH 2 )n with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R7 and R 8 are both hydrogen; R and R 8 , which may be the same or different, each independently 10 represent hydrogen, C 16 alkyl, cycloC 3 12 alkyl, C 2
.
6 alkenyl, cycloC 312 alkyl-CI.ealkyl, aryl, aryl-C1.6alkyl, heteroaryl, or heteroaryl-CI 6 alkyl; or R 7 and R3 may together represent -(CH 2 )m- with m being 4, 5 or 6; 15 R 9 and R 10 , which may be the same or different, each independently represent hydrogen, C 1
.
6 alkyl, hydroxy, or C 1
.
6 alkoxy; R" represents hydrogen, C1.
6 alkyl, C 2
-
6 alkenyl, aryl; aryl-C 1
.
6 alkyl, aryl-C 2
-
6 alkenyl, heteroaryl, heteroaryl-C1.
6 alkyl, C1.
6 alkylamino, 20 di-C 1
.
6 alkylamino, cycloC3.- 2 alkylamino, di-C 1
.
6 alkylamino-C 1
.
6 alkyl, arylamino, aryl-Ci- 6 alkylamino, aryl-C 2
.
6 alkenylamino, N-aryl-N-C 1
.
6 alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, cycloC 3 .i 2 alkyl, or cycloC 3
.
2 alkyl-CI 6 alkyl, wherein the cycloC31 2 alkyl is optionally 25 unsaturated and wherein one carbon atom in the cycloC 3
-
12 alkyl moiety may be replaced by an oxygen atom or an NR' 2 -moiety; R1 2 represents hydrogen, C 1 e 6 alkyl, aryl, heteroaryl, aryl-C 1
.
6 alkyl or heteroaryl-C6alkyl; 30 wherein the term "C 1
.
6 alkyl" represents straight or branched chain alkyl groups; the term "C 2
-
6 alkenyl" represents straight or branched chain alkenyl groups; the term "C 2
.
6 alkyny" represents straight or branched chain alkynyl groups; the term "cycIoC3.2alkyl" represents monocyclic, 6 WO 2005/082856 PCT/GB2005/000717 bicyclic or tricyclic alkyl groups including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl; the term "aryl" represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected independently from a halogen, 5 trifluoromethyl, C 1
.
6 alkyl, C 2
-
6 alkenyl, C 1
.
6 alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C 1
.
6 alkoxycarbonyi, C 1
.
6 alkylamino, di-C 1
.
alkylamino, piperidinyl, morpholinyl, and pyridyl; the term "biaryl" represents biphenylene, preferably 4,4'-biphenylene, wherein one or both phenyl rings may optionally be substituted independently by one or 10 more of the substituents independently selected from a halogen, trifluoromethyl,I C 1
.
6 alkyl, C 2
-
6 alkenyl, C 1
_
6 alkoxy, amino, hydroxy, nitro, cyano, C 1 6 alkoxycarbonyl, C 16 alkylamino, di-Cl- 6 alkylamino, piperidinyl, morpholinyl, and pyridyl; the term "heteroaryl" represents an aromatic 5 6 membered ring comprising one to four heteroatoms selected from 15 oxygen, sulfur and nitrogen, and a 5-6 membered bicyclic ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more 20 substituents selected independently from a halogen, trifluoromethyl, C 16 alkyl, C 2
.
6 alkenyl, C 1 6 alkoxy, amino, hydroxy, nitro, cyano, C 1
.
6 alkoxycarbonyl, C 1
.
6 alkylamino, di-C 16 alkylamino, piperidinyl, morpholinyl, pyridyl, and aryl; heteroaryl may for example be furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, 25 oxadiazolyl, tetrazolyl, pyridinyl, pyrimidyl, benzofuryl, benzothiophenyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl and isoquinolyl; and the term "halogen" represents fluorine, chlorine, bromine and iodine; 30 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof; it being understood that: 7 WO 2005/082856 PCT/GB2005/000717 R2 may not represent unsubstituted phenyl or naphthyl; R2 may not represent substituted phenyl having at least one ortho substituent other than hydrogen, relative to the tetrahydroquinoline ring of 5 formula IA to which the phenyl is attached; R2 may not represent dimethylamino; if one of R 5 and R 6 and one of R 7 and R3 together represent -(CH 2 )n- with n 10 being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R 7 and R 8 are both hydrogen, then R 2 may also be halogen; if R 3 , R 4 , R 5 , R 6 , R 7 , R", R 9 and R' 0 all represent hydrogen at the same time, then R 2 may not represent C 2
-
6 alkyl; 15 if R3 is cyano, then R 2 may not represent methylthio or ethylthio;
R
7 and R" may not represent furyl; 20 and the compound of Formula IA may not represent: 2-Benzyloxy-7,8-dihydro-6H-quinoline-5-one, 2-Phenoxy-7,8-dihydro-6H quinolin-5-one, 2-(1 H-Indol-3-yi)-7,8-dihydro-6H-quinolin-5-one, 2-(1 H-Indol 3-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Thiophen-2-yl-7,8 25 dihydro-6H-quinolin-5-one, 2-Ethoxy-7,8-dihydro-6H-quinolin-5-one, 7,7 Dim ethyl-2-(6-methyl-pyridin-3-ylmethylsufanyl)-5-oxo-5,6,7, 8-tetrahydro quinoline-3-carbonitrile, 2-(1 H-Benzoimidazol-2-ylmethylsuifanyl)-7,7 dim ethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 2-(4-Methoxy phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-(4-Chloro-phenyl)-7,7-dimethyl-7,8 30 dihydro-6H-quinolin-5-one, 2-(4-Fluoro-phenyl)-7,8-dihydro-6H-quinolin-5 one, 2-(4-isopropyl-phenyl)-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, or 2-Cyclohexyl-7,8-dihydro-6H-quinolin-5-one. 8 WO 2005/082856 PCT/GB2005/000717 [0012] such a compound of Formula IA, wherein R 3 represents hydrogen, cyano or nitro; [0013] such a compound of Formula IA, wherein R 4 represents hydrogen; 5 [0014] such a compound of Formula IA, wherein R 5 and R 6 , which may be the same or different, each independently represent hydrogen or C 1 .Ealkyl, and R7 and R8, which may be the same or different, each independently represent hydrogen, C 1
.
6 alkyl or cycloC 3 -1 2 alkyl, or wherein one of R5 and R 6 10 and one of R and R3 together represent -(CH 2 )n- with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R7 and R 8 are both hydrogen, or wherein R 7 and Ra may together represent -(CH 2 )m- with m being 4, 5 or 6; [0015] such a compound of Formula IA, wherein R 5 and R , which may be 15 the same or different, each independently represent hydrogen, methyl, or ethyl; [0016] such a compound of Formula IA, wherein R 7 and R 8 , which may be the same or different, each independently represent hydrogen, methyl, or 20 cyclohexyl. [00171 such compound of Formula IA, wherein one of R 5 and R 6 and one of
R
7 and R3 together represent -(CH 2 )n- with n being 4, while the remaining of
R
5 and R 6 as well as R 7 and R 8 are both hydrogen; 25 [00181 such compound of Formula IA, wherein R 7 and Ra together represent
-(CH
2 )m- with m being 5 or 6; [0019] such compound of Formula IA, wherein R9 and R"), which may be the 30 same or different, each independently represent hydrogen or C 1 .. ealkyl; [0020] such compound of Formula IA, wherein R 9 and R 10 , which may be the same or different, each independently represent hydrogen or methyl; 9 WO 2005/082856 PCT/GB2005/000717 [0021] such compound of Formula IA, wherein R 2 represents Cl.
6 alkylthio,
C
4
.
6 alkenylthio or cycloC3-1 2 alkylthio; R 3 represents hydrogen or cyano; R4 represents hydrogen, halogen, nitro or C 16 alkoxy; R and R , which may be the same or different, each independently represent hydrogen or C 1 6 alkyl; 5 R and R3, which may be the same or different, each independently represent hydrogen, C 1
-
6 alkyl or cycloC 3
.
1 2 alkyl or R and Ra may together represent -(CH 2 )m- with m being 4, 5 or 6; and R 9 and R 10 , which may be the same or different, each independently represent hydrogen or C 16 alkyl; 10 [0022] such compound of Formula IA, wherein R 2 represents C 2 -ealkoxy, cycloC 3
.
12 alkoxy, cycloC 3 -1 2 alkyl-Cl6alkoxy, aryloxy, aryl-C 16 alkoxy or
C
16 alkoxy-C- 6 alkyl; R 3 represents hydrogen or cyano;R 4 represents hydrogen, halogen, nitro or C 1 .ealkoxy; R 5 and R , which may be the same or different, each independently represent hydrogen or C 16 alkyl; R 7 and R 8 , 15 which may be the same or different, each independently represent hydrogen, C 16 alkyl or cycloC 3
-
1 2 alkyl or R 7 and R3 may together represent
-(CH
2 )m 1 - with m being 4, 5 or 6; and R 9 and R1 0 , which may be the same or different, each independently represent hydrogen or C 1
.
6 alkyl; 20 [00231 such compound of Formula IA, wherein R 2 represents C 1
.
6 alkylamino, di-C 1 6 alkylamino, cycioC 3
-
1 2 alkylamino, cycloC 3 -1 2 alkyl-C 16 alkylamino, di-C 1 6 alkylamino-C 1 6 alkyl, Clsalkoxy-C2- 6 alkylamino, arylamino, aryl-C 1 .6 alkylamino, N-cycloC 3
..
2 alkyl-N-C1.
6 alkylamino, N-aryl-N-C 16 alkylamino, N-aryl-C 1
.
6 alkyl-N-Ciealkylamino, wherein the aryl moieties may be 25 unsubstituted or substituted by one or two substituents, each independently selected from methoxy, cyano, halogen, hydroxy, methyl, pyridyl, morpholinyl and piperidinyl; R 3 represents hydrogen or cyano; R 4 represents hydrogen, halogen, nitro or C 1
.
6 alkoxy; R 5 and R 6 , which may be the same or different, each independently represent hydrogen or C 16 alkyl; R and R3, 30 which may be the same or different, each independently represent hydrogen, C 16 alkyl or cycloC 3
-
12 alkyl, or R 7 and R8 may together represent
-(CH
2 )m- with m being 4, 5 or 6; and R 9 and R'", which may be the same or different, each independently represent hydrogen or C 1 6 alkyl; 10 WO 2005/082856 PCT/GB2005/000717 [0024] such a compound of Formula IA, wherein R 2 represents C 2
-
6 alkyl, cycloC 3 .1 2 alkyl, cycloC3-1 2 alkyl-C 1
.
6 alkyl, C 2
-
6 alkenyl or aryl-C 16 alkyl; R 3 represents hydrogen, cyano, nitro or morpholino; R 4 represents hydrogen, halogen, nitro or C 1 6 -alkoxy; R 5 and R 6 , which may be the same or different, 5 each independently represent hydrogen or CI 6 alkyl; R 7 and R 8 , which may be the same or different, each independently represent hydrogen, C1.6alkyl or cycloC 3
-
1 2 alkyl, or R 7 and R may together represent -(CH2)m- with m being 4, 5 or 6; and R 9 and R 1 0 , which may be the same or different, each independently represent hydrogen or C 1
.
6 alkyl; 10 [0025] such a cor-6pound of Formula IA, wherein R 2 represents aryl-C 2
-
6 alkynyl or heteroaryl-C 2
-
6 alkynyl, wherein the aryl moiety may be unsubstituted or substituted by one or two substituents each independently selected from methoxy, cyano, halogen, hydroxy and methyl and the 15 heteroaryl moiety may be unsubstituted or substituted by one or two substituents each independently selected from phenyl, methoxy, cyano, halogen, hydroxy and methyl; R 3 represents hydrogen, cyano or nitro; R 4 represents hydrogen; R9 and R , which may be the same or different, each independently represent hydrogen or C1- 6 alkyl; R 7 and R 8 , which may be the 20 same or different, each independently represent hydrogen, C 1
.
6 alkyl or cycIoC 3
-
12 alkyl, or R7 and R 8 may together represent -(CH 2 )m- with m being 4, 5 or 6; and R 9 and R 1 0 , which may be the same or different, each independently represent hydrogen or C1.
6 alkyl; 25 [0026] such a compound of Formula IA, wherein R 2 represents biaryl or heteroaryl-aryl, wherein the aryl moieties may be unsubstituted or substituted by one or two substituents each independently selected from methoxy, cyano, halogen, hydroxy and methyl; R 3 represents hydrogen, cyano or nitro; R 4 represents hydrogen; R 5 and R 6 , which may be the same 30 or different, each independently represent hydrogen or C 1
-
6 alkyl; R and R3, which may be the same or different, each independently represent hydrogen, C 1
.
6 alkyl or cycloC 3
-
1 2 alkyl, or R 7 and R 8 may together represent
-(CH
2 )m- with m being 4, 5 or 6; and R 9 and R 1 0 , which may be the same or different, each independently represent hydrogen or C 1
.
6 alkyl; 11 WO 2005/082856 PCT/GB2005/000717 [0027] such a compound of Formula IA, wherein R 2 represents aryl heteroaryl or heteroaryl-heteroaryl, wherein the aryl moieties and the heteroaryl moieties that are not directly attached to the tetrahydroquinoline 5 ring of formula IA may be unsubstituted or substituted by one or two substituents each independently selected from methoxy, cyano, halogen, hydroxy, methyl, pyridyl, morpholinyl and piperidinyl; R represents hydrogen, cyano or nitro; R 4 represents hydrogen; R 5 and R , which may be the same or different, each independently represent hydrogen or C 1
.
6 alkyl; 10 R 7 and R", which may be the same or different, each independently represent hydrogen, C 1 .ealkyl or cycloC 3
.
1 2 alkyl or R 7 and RB may together represent -(CH 2 )m- with m being 4, 5 or 6; and R 9 and R 10 , which may be the same or different, each independently represent hydrogen or C 1 6 alkyl; 15 [0028] such a compound of Formula IA, wherein R 2 represents halogen, aryl, heteroaryl, arylamino, aryl-C 1
.
6 alkylamino, cycloC 3
-
1 2 alkyl, piperidino, 4 arylpiperidino, morpholino, piperazino, 4-C 1
.
6 alkylpiperazino, or 4 arylpiperazino, wherein the aryl moieties and the heteroaryl moieties may be unsubstituted or substituted by one or two substituents, each independently 20 selected from methoxy, cyano, halogen, hydroxy and methyl; one of R5 and R and one of R 7 and R together represent -(CH 2 )n- with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R 7 and R 8 are both hydrogen; R 3 represents hydrogen, cyano or nitro; R 4 represents hydrogen; and R 9 and R1 0 , which may be the same or different, each independently represent 25 hydrogen or C 1 6 alkyl; [0029] Moreover, a method-of-treating a living animal, including a human for a condition associated with glutamate induced excitation of the CNS comprising the step of administering to the living animal an amount of an 30 mGluR antagonist selected from those of formula IA
R
4 O R R R 6 1I R IA
R
2 N R 8
R
10
R
9 12 WO 2005/082856 PCT/GB2005/000717 wherein
R
2 represents C 1
.
6 alkyl, cycloC3.- 2 alkyl, cycloC 3
.
12 alkyl-C 1
-
6 alkyl, 5 C 2
-
6 alkenyl, C 2
-
6 alkynyl, aryl, biaryl, aryl-heteroaryl, heteroaryl heteroaryl, heteroary-aryl, aryl-C 1
.
6 alkyl, aryl-C 2
-
6 alkenyl, aryl
C
2
-
6 alkynyl, heteroaryl, heteroaryl-C 1
.
6 alkyl, heteroaryl-C 2
-
6 alkenyl, heteroaryl-C 2
.
6 alkynyl, 2,3-dihydro-1 H-indenyl, C1.ealkoxy, hydroxy
C
2
.
6 alkoxy, cycIoC3-1 2 alkoxy, cycIoC 3 -1 2 alkyl-C 1
.
6 alkoxy, aryloxy, aryl 10 C 1
.
6 alkoxy, C 1
.
6 alkoxy-C 1 .salkyl, C 1
.
6 alkylthio, C 4
.
6 alkenylthio, cycloC 3
-
1 2 al ylthio, cycIoC 3
..
2 alkyl-C 1
.
6 alkylthio, cycloC3- 1 2 alkyl
C
3
.
6 alkenylthio, C 1 .ealkoxy-C 1
.
6 alkylthio, C-6alkoxy-C 3
-
6 alkenylthio, aryl-C1.salkylthio, aryl-C 3
.
6 alkenylthio, heteroaryl-C 1
.
6 alkylthio, C 1 -6 alkylsulfonyl, cycloC 3
-
12 alkyl-C 1
.
6 alkylsulfonyl, aryl-C 1
.
6 alkylsulfonyl, 15 C 1
.
6 alkylamino, di-C 1
.
6 alkylamino, cycloC 3
..
12 alkylamino, C 16 alkoxy cycloC 3
.
12 alkylamino, cycloC 3
-
12 alkyl-C 1
.
6 alkylamino, di-C 1
.
6 alkylamino-C 1
.
6 alkyl, C 1
.
6 alkoxy-C 2
-
6 alkylamino, arylamino, aryl Ci.
6 alkylamino, N-cycloC 3
.
12 alkyl-N-C 6 alkylamino, N-aryl-N Cle 6 alkylamino, N-arylC 1
.
6 alkyl-N-C 1
.
6 alkylamino, 2-indanylamino, 20 1,2,3,4-tetrahydroisoquinolin-2-y, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C 1 .ealkylpiperazino, 4-arylpiperazino, hexamethyleneimino,.benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, heteroaryl-C 1
.
6 alkoxy, heteroarylamino, heteroaryl-C 1
.
6 alkylamino, 25 -NHC(=O)-R", -NHSO 2 -R", -NHC(=0)OR, -C(=O)NH-R", or
-C
1 6 alkyl-C(=O)NH-R", wherein the cycloC 3
.
12 alkyl is optionally unsaturated and wherein one carbon atom in the cycIoC 312 alkyl moiety may be replaced by an oxygen atom or an NR' 2 -moiety; 30 R 3 represents hydrogen, cyano, nitro, halogen, C 1
.
6 alkyl, CF 3 , heteroaryl, 2,3-dihydro-1 H-indenyl, hydroxy, C 16 alkoxy, pyrrolidino, piperidino, or morpholino;
R
4 represents hydrogen, halogen, nitro, C 1
.
6 alkoxy, or hydroxy 13 WO 2005/082856 PCT/GB2005/000717
C
2
-
6 alkoxy;
R
5 and Rr, which may be the same or different, each independently represent hydrogen, hydroxy, C 1
.
6 alkyl; cycIoC 3
-
12 alkyl, C 2
.
6 alkenyl, 5 C 1 .Ealkoxy, Ci.
6 alkoxy-C 1
-
6 alkyl, C 1 .ealkylthio, C 3
.
6 alkenylthio, CI-6 alkylamino, di-C 1
.
6 alkylamino, cycloC 3
-
12 alkylamino, di-C 1
.
6 alkylaminoC 1
.
6 alkyl, aryl-C1.salkylamino, aryl, aryl-C 1
.
6 alkyl, or ary-IC2- 6 alkenyl; 10 or one of R and R 6 and one of R 7 and R3 together represent -(CH 2 )n with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R7 and R3 are both hydrogen;
R
7 and R 8 , which may be the same or different, each independently 15 represent hydrogen, C 1
.
6 alkyl, cycloC 3 -1 2 alkyl, C 2
-
6 alkenyl, cycIoC 3 -1 2 alkyl-C 1
.
6 alkyl, aryl, aryl-C1.
6 alkyl, heteroaryl or heteroaryl
C
1
.
6 alkyl; or R 7 and R 8 may together represent -(CH 2 )m- with m being 4, 5 or 6; 20
R
9 and R 10 , which may be the same or different, each independently represent hydrogen, C 1
.
6 alkyl, hydroxy, or C 1
.
6 alkoxy; R" represents hydrogen, C 1
.
6 alkyl, C 2
-
6 alkenyl, aryl; aryl-C1.
6 alkyl, 25 aryl-C 2
-
6 alkenyl, heteroaryl, heteroaryl-C1.ealkyl, C 1
.
6 alkylamino, di-C 1
.
6 alkylamino, cycloCa 12 alkylamino, di-C 1
.
6 alkylamino-C 1
.
6 alkyl, arylamino, aryl-C 1 .ealkylamino, aryl-C 2
-
6 alkenylamino, N-aryl-N-C 1 .6 alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, cycloC 3 -1 2 alkyl, or 30 cycloC 3 -1 2 alkyl-C1.
6 alkyl, wherein the cycloC 3 -1 2 alkyl is optionally unsaturated and wherein one carbon atom in the cycloC 3
.
12 alkyl moiety may be replaced by an oxygen atom or an NR1 2 -moiety; 14 WO 2005/082856 PCT/GB2005/000717 R1 2 represents hydrogen, C 1
.
6 alkyl, aryl, heteroaryl, aryl-C 1
.
6 alkyl or heteroaryl-C 1
.
6 alkyl; wherein the term "C 1
-
6 alkyl" represents straight or branched chain alkyl 5 groups; the term "C 2
-
6 alkenyl" represents straight or branched chain alkenyl groups; the term "C 2
-
6 alkynyl" represents straight or branched chain alkynyl groups the term "cycloC 3 .1 2 alkyl" represents monocyclic, bicyclic or tricyclic alkyl groups including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl; the term 10 "aryl" represents phenyl or naphthyl, or phenyl substituted by one or more substituents selected independently from a halogen, trifluoromethyl, C 1
.
6 alkyl, C 2
-
6 alkenyl, CS- 6 alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C 1 .ealkoxycarbonyl, C1.
6 alkylamino, di-C 1
.
6 alkylamino, piperidinyl, morpholinyl, and pyridyl; the term "biaryl" 15 represents biphenylene, preferably 4,4'-biphenylene, wherein one or both phenyl rings may optionally be substituted independently by one or more of the substituents independently selected from a halogen, trifluoromethyl, C 1
.
6 alkyl, C 2
-
6 alkeny, C 1
.
6 alkoxy, amino, hydroxy, nitro, cyano, C 1
.
6 alkoxycarbonyl, C 1
.
6 alkylamino, di-C 1
.
6 alkylamino, piperidinyl, 20 morpholinyl, and pyridyl; the term "heteroaryl" represents an aromatic 5 6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a 5-6 membered bicyclic ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring comprising 25 one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected independently from a halogen, trifluoromethyl, C 1
.
6 alkyl, C 2
-
6 alkenyl, C 1
.
6 alkoxy, amino, hydroxy, nitro, cyano, C1.6 alkoxycarbonyl, C 1
.
6 alkylamino, di-C1.
6 alkylamino, piperidinyl, 30 morpholinyl, pyridyl, and aryl; heteroaryl may for example be furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidyl, benzofuryl, benzothiophenyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl and 15 WO 2005/082856 PCT/GB2005/000717 isoquinolyl; and the term "halogen" represents fluorine, chlorine, bromine and iodine; it being understood that if one of R 5 and R 6 and one of R 7 and R 8 together 5 represent -(CH 2 )n- with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R 7 and Ra are both hydrogen, then R 2 may also be halogen; and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof, 10 which is effective for alleviation of the condition; [0030] such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising the compound in 15 combination with one or more pharmaceutically-acceptable diluents, excipients, or carriers; [0031] such a method wherein the condition associated with excessive glutamate induced excitation of the CNS is selected from the group 20 consisting of AIDS-related dementia, Alzheimer's disease, Creutzfeld Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving B-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as 25 amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, vascular and frontal lobe dementia, eye injuries, eye disorders (e.g. glaucoma, retinopathy), head and spinal cord injuries, trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting 30 from cardiac arrest, stroke, bypass operations or transplants), seizures, convulsions, epliepsy, glioma and other tumours, inner ear insult (e.g. in tinnitus, sound or drug-induced), L-dopa-induced and tardive dyskinesias, Wilson's disease. 16 WO 2005/082856 PCT/GB2005/000717 [0032] such a method wherein the condition associated with excessive glutamate induced excitation of the CNS is selected from the group consisting of addiction (nicotine, alcohol, opiate, cocaine, amphetamine obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic 5 disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome and hyperactive children, autism, seizures, convulsions, epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections, Down syndrome), depression (including that resulting from Borna virus infection) and bipolar manic-depressive disorder, 10 drug tolerance e.g. to opioids, dyskinesia (e.g. L-Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain (chronic and acute), Parkinson's disease, post traumatic stress disorder, schizophrenia, spasticity, tinnitus, Tourette's syndrome, urinary 15 incontinence and vomiting, Wilson's disease. [0033] Further, a pharmaceutical composition comprising, together with one or more pharmaceutically acceptable excipients or vehicles, a compound selected from those of Formula IA 20
R
4 0 R R R 6 R IA . R 2 N Ra
R
10
R
9 25 wherein
R
2 represents C 2
-
6 alkyl, cycloC3-1 2 alkyl, cycloC 3 -1 2 alkyl-C 1
.
6 alkyl,
C
2
.
6 alkenyl, C 2
-
6 alkynyl, aryl, biaryl, aryl-heteroaryl, heteroaryl heteroaryl, heteroaryl-aryl, aryl-C1.ealkyl, aryl-C 2
-
6 alkenyl, aryl 30 C2- 6 alkynyl, heteroaryl, heteroaryl-C 1 .ealkyl, heteroary-C 2
-
6 alkenyl, heteroary-C 2 .ealkynyl, 2,3-dihydro-1 H-indenyl, C 2 .alkoxy, hydroxy
C
2 -ealkoxy, cycloC 3
-
12 alkoxy, cycloC3.
12 alkyl-C 1 .ealkoxy, aryloxy, aryl
C
1 .ealkoxy, C 1
.
6 alkoxy-C 1 .ealkyl, C 1
.
6 alkylthio, C4.
6 alkenylthio, cycloC 3 -1 2 alkylthio, cycloC 3 1 2 alkyl-C1.
6 alkylthio, cycloC 3
.
12 alkyl 17 WO 2005/082856 PCT/GB2005/000717
C
3
-
6 alkenylthio, C1.
6 alkoxy-C 1
.
6 alkylthio, CI-6alkoxy-C3.ealkenylthio, aryl-C 3
.
6 alkenylthio, heteroaryl-C 1
.
6 alkylthio, C 1
.
6 alkylsulfonyl, cycloC 3 .1 2 alkyl-C 1
.
6 alkylsulfonyl, aryl-C 1
.
6 alkylsulfonyl,
C
1 .salkylamino, di-C 1 ..alkylamino, cycloC3-1 2 alkylamino, C 1
.
6 alkoxy 5 cycloC 3 -1 2 alkylamino, cycIoC 3
-
12 alkyl-C 1
.
6 alkylamino, di-C 1
.
6 alkylamino-C 1
.
6 alkyl, C1.6alkoxy-C 2 -,5alkylamino, arylamino, aryl
C
1
.
6 alkylamino, N-cycloC 3 -1 2 alkyl-N-C 1 .salkylamino, N-aryl-N
C
1
.
6 alkylamino, N-aryI-C1..alkyl-N-C1.
6 alkylamino, 2-indanylamino, 1,2,3,4-tetrahydroisoquinolin-2-y, tetrahydrofuryl, pyrrolidino, 10 piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C 1 ..alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, heteroaryl-C 1
.
6 alkoxy, heteroarylamino, heteroaryl-C 1
.
6 alkylamino, -NHC(=O)-R", -NHSO 2 -R", -NHC(=O)OR, -C(=O)NH-R", or 15 -C 1 .alkyl-C(=O)NH-R 11 , wherein the cycloC 3
-
1 2 alkyl is optionally unsaturated and wherein one carbon atom in the cycloC 3
-
12 alkyl moiety may be replaced by an oxygen atom or an NR 12 -moiety;
R
3 represents hydrogen, cyano, nitro, halogen, C 1
.
6 alkyl, CF 3 , 20 heteroaryl, 2,3-dihydro-1H-indenyl, hydroxy, C 1
-
6 alkoxy, pyrrolidino, piperidino, or morpholino;
R
4 represents hydrogen, halogen, nitro, C 1
.
6 alkoxy, or hydroxy-C 2
-
6 alkoxy; 25
R
5 and R 6 , which may be the same or different, each independently represent hydrogen, hydroxy, C1.6alkyl; cycloC3-1 2 alkyl, C 2
-
6 alkenyl,
C
1 .ealkoxy, C1.ealkoxy-C1.ealkyl, C 1 .ealkylthio, C3.
6 alkenylthio, C 1 -6 alkylamino, di-C 1
.
6 alkylamino, cycloC 3 -1 2 alkylamino, di-C 1
.
6 30 alkylaminoC1.6alkyl, aryl-C 1 .ealkylamino, aryl, aryl-C 1
.
6 alkyl, or aryl-C 2
-
6 alkenyl; 18 WO 2005/082856 PCT/GB2005/000717 or one of R 5 and R 6 and one of R and R 8 together represent -(CH 2 )n with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R7 and R 8 are both hydrogen; 5 R 7 and R 8 , which may be the same or different, each independently represent hydrogen, CI 6 alkyl, cycloC 3
.
12 alkyl, C 2
-
6 alkenyl, cycloC 3
.
12 alkyl-C 1
.
6 alkyl, aryl, aryl-C 1
.
6 alkyl, heteroaryl, or heteroaryl
C
1
.
6 alkyl; 10 or R 7 and R8 may together represent -(CH 2 )m- with m being 4, 5 or 6;
R
9 and R 10 , which may be the same or different, each independently represent hydrogen, C 1
.
6 alkyl, hydroxy, or C 1
.
6 alkoxy; 15 R" represents hydrogen, C 1
-
6 alkyl, C 2
-
6 alkenyl, aryl; aryl-C1.ealkyl, aryl-C 2
-
6 alkenyl, heteroaryl, heteroaryl-C 1
.
6 alkyl, C 1 .. salkylamino, di-C 1
_
6 alkylamino, cycloC 312 alkylamino, di-C 1
.
6 alkylamino-C 1 ..alkyl, arylamino, aryl-C 1
.
6 alkylamino, aryl-C 2
-
6 alkenylamino, N-aryl-N-C 1
.
alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, 20 benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, cycloC 3
-
12 alkyl, or cycIoC 3
-
1 2 alkylC 1
.
6 alkyl, wherein the cycloC 3
.
12 alkyl is optionally unsaturated and wherein one carbon atom in the cycloC 3
.
12 alkyl moiety may be replaced by an oxygen atom or an NR 12 -moiety; 25 R 12 represents hydrogen, C 1 .salkyl, aryl, heteroaryl, aryl-C 1 .alkyl or heteroary-C 1
.
6 alkyl; wherein the term "C 1
.
6 alkyl" represents straight or branched chain alkyl groups; the term "C 2
-
6 alkenyl" represents straight or branched chain 30 alkenyl groups; the term "C 2
-
6 alkynyl" represents straight or branched chain alkynyl groups the term "cycIoC 312 alkyl" represents monocyclic, bicyclic or tricyclic alkyl groups including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl; the term "aryl" represents phenyl or naphthyl, or phenyl substituted by one or 19 WO 2005/082856 PCT/GB2005/000717 more substituents selected independently from a halogen, trifluoromethyl, C 1
.
6 alkyl, C 2 -ealkenyl, C1.
6 alkoxy, amino, hydroxy, nitro, cyano, cyanomethyl, C 1
.
6 alkoxycarbonyl, C1.6alkylamino, di-C1.C alkylamino, piperidinyl, morpholinyl, and pyridyl; the term "biaryl" 5 represents biphenylene, preferably 4,4'-biphenylene, wherein one or both phenyl rings may optionally be substituted independently by one or more of the substituents independently selected from a halogen, trifluoromethyl, CIealkyl, C 2 -ealkenyl, C 1
.
6 alkoxy, amino, hydroxy, nitro, cyano, C 1
.
6 alkoxycarbonyl, C 1
.
6 alkylamino, di-C 1
.
6 alkylamino, piperidinyl, 10 morpholinyl, and pyridyl; the term "heteroaryl" represents an aromatic 5 6 membered fing comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a 5-6 membered bicyclic ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring comprising 15 one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected independently from a halogen, trifluoromethyl, C 1
.
6 alkyl, C 2
-
6 alkenyl, C1.
6 alkoxy, amino, hydroxy, nitro, cyano, C 1
.
6 alkoxycarbonyl, C 1
.
6 alkylamino, di-C 1
.
6 alkylamino, piperidinyl, 20 morpholinyl, pyridyl, and aryl; heteroaryl may for example be furyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidyl, benzofuryl, benzothiophenyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl and isoquinolyl; and the term "halogen" represents fluorine, chlorine, bromine 25 and iodine; and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof; 30 it being understood that: R2 may not represent unsubstituted phenyl or naphthyl; 20 WO 2005/082856 PCT/GB2005/000717 R2 may not represent substituted phenyl having at least one ortho substituent other than hydrogen, relative to the tetrahydroquinoline ring of formula IA to which the phenyl is attached; 5 R 2 may not represent dimethylamino; if one of R and R and one of R and R 8 together represent -(CH 2 )n- with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R 7 and R 8 are both hydrogen, then R 2 may also be halogen; 10 if R 3 , R 4 , R 5 , R 6 , R 7 , R", R 9 and R 10 all represent hydrogen at the same time, then R 2 may not represent C 2
-
6 alkyl; if R 3 is cyano, then R 2 may not represent methylthio or ethylthio; 15
R
7 and Ra may not represent furyl; and the compound of Formula IA may not represent: 20 2-Benzyloxy-7,8-dihydro-6H-quinoline-5-one, 2-Phenoxy-7,8-dihydro-6H quinolin-5-one, 2-(1H-indol-3-yl)-7,8-dihydro-6H-quinolin-5-one, 2-(1H-Indol 3-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Thiophen-2-yl-7,8 dihydro-6H-quinolin-5-one, 2-Ethoxy-7,8-dihydro-6H-quinolin-5-one, 7,7 Dimethyl-2-(6-methyl-pyridin-3-ylmethylsulfanyl)-5-oxo-5,6,7,8-tetrahydro 25 quinoline-3-carbonitrile, 2-(1 H-Benzoimidazol-2-ylmethylsulfanyl)-7,7 dim ethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 2-(4-Methoxy phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-(4-Chloro-phenyl)-7,7-dimethyl-7,8 dihydro-6H-quinolin-5-one, 2-(4-Fluoro-phenyl)-7,8-dihydro-6H-quinolin-5 one, 2-(4-Isopropyl-phenyl)-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 30 or 2-Cyclohexyl-7,8-dihydro-6H-quinolin-5-one. [0034] Specific compounds of Formula IA within the present invention include but are not limited to: 21 WO 2005/082856 PCT/GB2005/00071 7 7,7-Dimethyl-2-(2-m ethyl-allylsulfanyl)-5-oxo-5, 6,7,8-tetrahydroqu inoline-3 carbonitrile, 2-Isopropylsulfanyl-7, 7-dimethyl-5-oxo-5, 6,7, 8-tetrahydroquinol ine-3 carbon itrile, 5 7,7-Dimethyl-5-oxo-2-propylsulfanyl-5,6,7,8-tetrahydroquinoline-3 carbonitrite, 2-(2-Methyl-aI Iylsulfanyl)-5-oxo-5,6, 7, 8-tetrahydro-quinoline-3- carbonitrile, 2-Butylsuffanyl-7, 7-dimethyl-5-oxo-5,6, 7, 8-tetrahydroquinoline-3 carbonitri le, 10 7,7-Dimethyl-5-oxo-2-piperidin-1 -y1-5,6,7, 8-tetrahydroquinoline-3 carbonitrile, ' 2-Benzylamino-7, 7-dimethyl-5-oxo-5,6, 7,8-tetrahydroquinoline-3-carbonitrile, 7,7-Dimethyl-2-phenethyl-7,8-dihydro-6H-quiolil-5-ofle, 2-Cyclohexyloxy-7, 7-dimethyl-7, 8-dihydro-6H-qu inolin-5-one, 15 2-Isobutoxy-7 ,7-dimethyl-5,6, 7, 8-tetrahydroquinolin-5-one, 2-Isobutylsulfanyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3 carbonitrile, 2-Benzylamino-7,7-dimethyl-7,8-dihydro-6H-quiolil-5-ofle, 2-Benzyloxy-7,7-dimethyl-7,8-dihydro-6H-quiolil-5-ofle, 20 2-Benzyl-7, 7-dimethyl-7, 8-dihydro-6H-quinolin-5-one, 2-[2-(2-Methoxyphenyl)ethyl]-7, 8-dihydro-6H-quinolin-5-one, 2-Adamantan-1 -yI-6-propyl-7,8-dihydro-6H-quinolin-5-one, 7-Phenyl-2-pyidin-2-y-7,8-dihydro-6H-quilolil-5-ofle, 2-Benzyloxy-7-(4-chloro-pheny)-7,8-dihydro-6H-quilil-5-ofle, 25 2-Adamaritan-1 -yI-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 -one, 2-Adamantan-1 -yI-7,8-dihydro-6H-quinolin-5-one, 2-Isobutoxy-7-phenyl-7,8-dihydro-6H-quilolil-5-ofle, 2-.Phenoxy-7-phenyl-7, 8-dihydro-6H-quinolin-5-one, 2-.Phenethyl-7,8-dihydro-6H-quilolil-5-ofle, 30 2-.Benzyloxy-7-7-pentamethylefle-7,8-dihydro-6H-quilifle-5-ofle, 2-Adamantan-1 -yi-7-7-pentamethylene-7, 8-dihydro-6H-quinoline-5-one, 2-Ethoxy-7-7-pentamethylene-7, 8-dihydro-6H-quinoline-5-one, 2-(2-Hydroxyethoxy)-1 -yI-7-7-pentamethylene-7, 8-dihydro-6H-quinoline-5 one, 22 WO 2005/082856 PCT/GB2005/00071 7 2-Isopropyl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Benzyloxy-7-ethyl-7,8-dihydro-6H-quinolin-5-ofle, 7-(4-Dimethylam ino-phenyl)-2-hexyl-7,8-d ihydro-6H-quinolin-5-one, 2-Cyclohexyl-7-propyl-7, 8-dihydro-6H-quinolin-5-one, 5 2-(4-Methoxy-pheny)-6,6-dimethyl-7, 8-dihydro-6H-quinolin-5-one, cis, trans-6-Ethyl-2-(4-methoxy-phenyl)-cis,trans-6,8-diml ethyl-7, 8-dihydro 6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-7, 7-dimethyl-7, 8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-6-ethyl-7 ,8-dihydro-6H-quinolin-5-one, 10 2-(3-Methoxy-phenyl)-6-methyl-7, 8-dihydro-6H-quinolin-5-one, 2-Adamantan-1 -yI-6-ethyl-8-methyl-7, 8-dihydro-6H-quinolin-5-one, 2-Ethoxy-7-furan-2-yi-7, 8-dihydro-6H-quinolin-5-one, 2-Adamantan-1 -yI-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, (cis,trans) 2-Acfamantan-1 -yl-6-ethyl-8-methyl-7, 8-dihydro-6H-quinolin-5-one 15 and 2-adamantan-1 -yl-8-ethyl-6-methyl-7,8-d ihydro-6H -quinolin-5-one, cis,trans 6-Ethyl-2-hexyl-6, 8-dimethyl-7, 8-dihydro-6H-quinolin-5-one, 2-Cyclohexylmethyl-7 ,7-tetram ethylene-7, 8-dihydro-6H-quinolin-5-one 2-Hexyl-7-phenyl-7, 8-dihydro-6 H-quinolin-5-one, 2-Cyclohexyl-7-isopropyl-7, 8-dihydro-6H -quinolin-5-one, 20 2-Cyclohexyl-6-ethyl-6-methyl-7, 8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-6,,8-trimethyl-7, 8-dihydro-6H-quinolin-5-one, cis,trans 6-Ethyl-2-(3-methoxy-phenyl)-8-m ethyl-7,8-d ihyciro-6H-qu inolin-5 one and 8-ethyl-2-(3-methoxy-phenyl)-6-methyl-7,8-d ihydro-6H-quinolin-5 one, 25 cis 2-(3-M ethoxy-phenyl)-6, 8-dimethyl-7, 8-dihydro-6H-q uinolin-5-one, 2-(3-Methoxy-phenyl)-6,6-dimethyl-7, 8-dihydro-6H-quinolin-5-one, 2-H exyl-cis,trans-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-H exyl-7-propyl-7,8-dihydro-6H-quinolin-5-one, 6-Etyl--heyl-,8-dihydro-6H-quinolin-5-one, 30 2-Hexyl-6,6,8-trimethyl-7, 8-dihydro-6H-quinolin-5-one, 2-Hexyl-6,6-dimethyl-7, 8-dihydro-6H-quinolin-5-one, cis, trans-8-Ethyl-2-hexyl-6-m ethyl-7, 8-d ihydro-6 H-quino lin-5-one and cis, trans-6-ethyl-2-hexyl-8-m ethyl-7,8-dihydro-6H-quinolin-5-one, 2-H exyI-7-isopropyI-7,8-dihydro-6H-quinolin-5-one, 23 WO 2005/082856 PCT/GB2005/00071 7 2-(3-Methoxy-phenyl)-7, 7-tetramethylene-7,8-dihydro-6H-quinolin-5-one, 2-(4-Methoxy-phenyl)-6-propyl-7, 8-dihydro-6H-quiflolin-5-one, 2-(3-Methoxy-phenyl)-6-propyl-7 ,8-dihydro-6H-quinolin-5-one, 2-(4-Methoxy-phenyl)-6, 6, 8-trimethyl-7,8-dihydro-6H-quinoiin-5-one, 5 2-(4-Methoxy-phenyl)-7, 7-tetram ethylene -7 ,8-d ihydro-6H-qu inoli n-5-one, 2-Hexyl-7-(3-methoxy-phenyl)-7, 8-dihydro-6H-quinolin-5-one, 2-Hexyl-6,6-dimethyl-7, 8-dihydro-6H-quinolin-5-one, 2-Benzyl-7, 7-tetram ethylene-7, 8-dihydro-6H-quinolin-5-one, 2-Benzyl-6-propyl-7,8-d ihydro-6H-quinolin-5-one, 10 2-Benzyl-6-ethyl-7,8-dihydro-6H-quinolil-5-ofle, 2-Benzyl-7-propyl-7 ,8-dihydro-6H-quinolin-5-one, 7-Ethyl-2-(4-m ethoxy-phenyl)-7,8-dihydr-6H-quilolifl-5-ole, 2-(4-Methoxy-phenyl)-6, 8-d imethyl-7, 8-dihydro-6H-quinolin-5-one, 2-(4-Methoxy-phenyO)-8-methyl-6-propy-7, 8-dihydro-6 H-quinolin-5-one, 15 2-Benzyl-6,6-dimethyl-7, 8-dihydro-6H-quinolin-5-one, 2-.Benzyl-6,6,84trimethyl-7,8-dihydro-6H-quilolifl-5-ofle, 2-Benzyl-7-ethyl-7,8-dihydro-6H-quinolil-5-ole, (cis, trans) 2-Benzyl-6-ethyl-8-methyl-7,8-dihydro-6H -quinolin-5-one and 2 benzyl-8-ethyl-6-methyl-7, 8-dihydro-6H-quinolin-5-one, 20 2-Cyclohexylmethyl-7, 7-dimethyl-7, 8-dihydro-6H-quinofin-5-one, 2-Cyclohexylmethyl-7-ethyl-7, 8-dihydro-6H-quinolin-5-one, 2-Cyclohexylmethyl-6, 6-dimethyl-7,8-dihydro-6H-qu inol in-5-one, 2-Cyclohexylmethyl-6-ethyl-7, 8-dihydro-6H-quinolin-5-one, 7-Isopropyl-2-pyridin-3-yI-7, 8-dihydro-6H-quinolin-5-one, 25 5-Oxo-2-phenylethynyl-5,6, 7, 8-tetrahydro-quinoline-3-carbonitri le, 2-B iphenyl-4-yI-7, 8-dihydro-6H-quinolin-5-one, 2-eyaio77dmty--x-,,,8ttayr-unln--abntie 2-(4-Methoxy-phenylam ino)-7,7-dimethyl-7,8-dihydro-6H-uiolifl-5-ofle, 7,7-DimethyI-5-oxo-2-[(tetrahydro-fural-2-ylmethyI)-ailo]-5 1 6,7 ,8 30 tetrahydro-quinoline-3-carbolitrile, 2-Cyclopentylamino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 2-(2-Methoxy-ethylam ino)-5-oxo-5,6, 7,8-tetrahydro-quinoline-3-carbolitri le, 2-(B enzyl-m ethyl-am ino)-5-oxo-5,6,7, 8-tetrahydro-quinoline-3-carbonitrile, 24 WO 2005/082856 PCTGB2005OOO71 7 5-Oxo-2-[(tetrahydro-furan-2-ylmethyl)-am ino]-5,6, 7,8-tetrahydro-quinoline 3-carbonitrile, 2-Cyclohexylamino-5-oxo-5,6, 7, 8-tetrahydro-quinoline-3-carbonitri le, 5-Oxo-2-[(pyridin-2-ylmethyl)-am ifl]-5r6,7, 8-tetrahydro-quinoline-3 5 carbonitrile, 2-Azepan-1 -yI-5-oxo-5,6, 7,8-tetrahydro-quinoline-3-carbonitrile, 2-(Cyclohexyl-methyl-amino)-7, 8-dihydro-6H-quinolin-5-ofle, 2-Phenylam ino-7, 8-dihydro-6H-quinolin-5-one, 2-(Cyclohexyl-methyl-amino)-7,7-dimethyl-7, 8-dihydro-6H-quinolin-5-one, 10 2-(B enzyi-m ethyi-am ino)-7, 7-dim ethyl-5-oxo-5, 6,7, 8-etrahydro-qu inoline-3 carbonitrile, 7, 7-DimethyI-5-oxo-2-[(pyridin-3-ylmethy)-al1ino]-5, 6,1, 8-tetrahydro quinoline-3-carbonitrile, 7, 7-Dimethyl-5-oxo-2-(4-phenyl-piperazil-1 -yI)-5, 6,7, 8-tetrahydro-qu inoline 15 3-carbonitrile, 2-Azepan-1 -yI-7, 7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Phenyl-piperazin-1 -yi)-7,8-dihydro-6H-quinolin-5-one, 2-Phenylethynyl-7,8-dihydro-6H-quiolil-5-ofle, 7,7 -Dimethyl-2-( I -phenyl-ethylamino)-7, 8-dihydro-6H-quinolin-5-one, 20 2-(3,5-D imethoxy-benzyam ino)-7,8-d ihydro-6 H-qu ilil-5 -one, 2-(3,5-Difluoro-benzylamino)-7,8-dihydro-6H-quilil-5-ofle, 2-B iphenyl-4-yl-5-oxo-5,6,7, 8-tetrahydro-quinoline-3-carbflitrile, 5-Oxo-2-(5-phenyl-thiophen-2-y)-5,6, 7,8-tetrahydro-quinoline-3-carbon itri le, 5-Oxo-2-(1 -phenyl-ethylamino)-5,6, 7, 8-tetrahydro-quinoline-3-carbon itrile, 25 2-(3-Fluoro-benzylamino)-7,8-dihydro-6H-quilil-5-ofle, 3-[(5-Oxo-5,6,7, 8-tetrahydro-quinolin-2-ylam ino)-methyl]-benzon itrile, 2-Phenylam ino-6,7,8,9, 9a, 1 O-hexahydro-5aH-benzo[glquinolin-5-ofle, 2-(l -Phenyl-ethylamino)-6, 7,8,9,9a, 1 0-hexahydro-5aH-benzo~g]quinolin-5 one, 30 2-(Cyclohexyl-methyl-alilo)-6, 7,8, 9,9a, I 0-hexahydro-5aH benzo[g]quinolil-5-ofle, 2-(4-Pheny-piperazin-1 -yI)-6,7,8,9, 9a, I 0-hexahydro-5aH-benzo[glquinolin 5-one, 25 WO 2005/082856 PCT/GB2005/000717 6-Ethyl-2-(2-m ethoxy-phenyl)-6-methyl-7, 8-dihydro-6H-quinolin-5-one hydrochloride, 2-Benzyl-7, 8-dihydro-6H-quinolin-5-one, 7, 7-Dimethyl-2-styryl-7, 8-dihydro-6H -quinolin-5-one, 5 2-Pyridin-3-ylethynyl-7 ,8-dihydro-6H-quinolin-5-one, 2-m-Tolylethynyl-7, 8-dihydro-6H-quinolin-5-one, 2-(3-Hydroxy-phenylethynyl)-7, 8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenylethynyl)-7, 8-dihydro-6H-quinolin-5-one, 2-3Fur-hnltyy)78dhdo6-unln5oe 10 2-(3-Chloro-phenylethynyl)-7, 8-dihydro-6H-quinolin-5-orie, 2-(3-Bromo-phenylethynyI)-7, 8-dihydro-6H-quinolin-5-one, 3-(5-Oxo-5,6, 7, 8-tetrahydro-qu inolin-2-ylethynyl)-benzon itrile, 2-Thiazol-5-yIethynyl-7,8-dihydro-6H-quilifl-5-ofle, 2-Oxazol-5-yiethynyl-7, 8-dihydro-6 H-quinolin-5-one, 15 2-(3-Methoxy-4-pyridin-3-yI-phenyl)-7, 8-dihydro-6H-quinouin-5-one, 2-(3-Methoxy-4-pyridin-2-yI-phenyl)-7, 8-dihydro-6 H-qu inolin-5-one, 2-Phenylethynyl-6, 7,8, 9,9a, I 0-hexahydro-5aH-benzo[g]quinolin-5-one, 2-Bromo-6,7, 8,9, 9a, I 0-hexahydro-5aH-benzo[gjquinolil-5-ofle, 2-Chloro-3-fluoro-6,7, 8,9, 9a, I 0-hexahydro-5aH-benzo[g]quinolin-5-one, 20 3-(5-Oxo-5,5a,6,7, 8,9,9a, 1 0-octahydro-benzo[glquinolin-2-y)-belzonitrile, 2-Pyridin-3-yI-6,7, 8,9, 9a, 1 0-hexahydro-5aH-benzo[g]quinolin-5-ofle, 2-P iperidin-1 -yI-6,7,8, 9,9a, 1 0-hexahydro-5aH-benzo~g]quinolin-5-ofle, 4-Chloro-5-oxo-2-(4-phenyl-piperazil-1 -yl)-5,6,7, 8-tetrahydro-quinoline-3 carbonitrile, 25 4-.Bromo-5-oxo-2-(4-pheflyl-piperazifl-I -yl)-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 4-Methoxy-5-oxo-2-(4-phenyl-piperazil-1 -yl)-5,6, 7,8-tetrahydro-quinoline-3 carbonitrile, 4-Ethoxy-5-oxo-2-(4-phenyl-piperazin-I -yl)-5,6, 7 ,8-tetrahydro-quinoline-3 30 carbonitrile, 4-Hydroxymethoxy-5-oxo-2-(4-phenfli-piperazifl-l -yI)-5,6,7 ,8-tetrahydro quinoline-3-carbonitrile, 4-Hydroxym ethoxy-7,7-dimethyl-5-oxo-2-(4-phel-piperazil-1 -yI)-5,6, 7,8 tetrahydro-quinoline-3-Carboflitri le, 26 WO 2005/082856 PCT/GB2005/00071 7 4-Ethoxy-7 ,7-dimethyl-5-oxo-2-(4-phenyl-piperazil-1 -yi)-5,6, 7,8-tetrahydro quinoiine-3-carbonitrile, 4-Methoxy-7, 7-dimethyl-5-oxo-2-(4-phenyl-piperazin-1 -yI)-5, 6,7, 8-tetrahydro quinoline-3-carbonitrile, 5 4-Chloro-7 ,7-dim ethyl-5-oxo-2-(4-phenyl-piperazin-1 -yi)-5,6,7, 8-tetrahydro quinoline-3-carbonitrile, 4-Bromo-7, 7-dimethyl-5-oxo-2-(4-pheny-piperazil-1 -yi)-5, 6 1 7 , 8-tetrahydro quinoline-3-carbonitrile, 4-Bromo-7,7-dimethyl-5-oxo-2-(4-pheny-piperidil-1 -yI)-5,6,7,8-tetrahydro 10 quinoline-3-carbonitrile, 4-Chloro-7 ,7-dim ethyl-5-oxo-2-(4-pheny-piperidin-1 -yi)-5,6, 7 , 8-tetrahydro quinoline-3-carbonitrile, 4-Methoxy-7, 7-dimethyl-5-oxo-2-(4-phenyl-piperidil -yI )-5,6, 7, 8-tetrahydro quinoline-3-carbonitrile, 15 4-Ethoxy-7 ,7-dimethyl-5-oxo-2-(4-phenyi-piperidil-I -yI)-5,6,7, 8-tetrahydro quinoline-3-carbonitrile, 4-(2-Hydroxy-ethoxy)-7, 7-dimethyl-5-oxo-2-(4-phelyl-piperidil-1 -yI)-5, 6,7,8 tetra hydro-qu inoline-3-carbonitrile, 3-Chloro-7,7-dimethyl-2-(4-phely-piperidifl-1 -yI)-7,8-dihydro-6H-quinolin-5 20 one, 3-Bromo-7,7-d imethyl-2-(4-pheny-piperidifl-1 -yI)-7 ,8-dihydro-6H-quinolin-5 one, 3-Fluoro-7,7-dimethyl-2-(4-phel-piperidil-1 -yI)-7,8-dihydro-6H-quinolin-5 one, 25 3-Methoxy-7 ,7-dimethyl-2-(4-pheny-piperidil-1 -yI)-7 ,8-dihydro-6H-quinolin 5-one, 7, 7-Dimethyl-3-nitro-2-(4-pheny-piperidil-1 -yI)-7, 8-dihydro-6H-quinol in-5 one, 7,7-Dimethyl-3-nitro-2-(4-phely-piperazil-1 -yI)-7, 8-dihydro-6H-quinolin-5 30 one, 3-Fluoro-7,7-dimethyI-2-(4-phenyi-piperazin-1 -yI)-7, 8-dihydro-6H-quinolin-5 one, 3-B romo-7, 7-dimethyl-2-(4-phenyl-piperazin-1 -yl)-7, 8-dihydro-6H-quinolin-5 one, 27 WO 2005/082856 PCTGB2005OOO71 7 3-Chloro-7, 7-dim ethyl-2-(4-phenyl-piperazin-1 -yI)- 7 , 8-dihydro-6H-quinol in-5 one, 3-Methoxy-7,7-dimethyl-2-(4-pheny-piperazil-1 -yI)-7, 8-dihydro-6H-quinolin 5-one, 5 2-[4-(4-Methoxy-phenyl)-piperazin-1 -yI]- 7 , 7-dimethyl-5-oxo-5,6,7, 8 tetrahydro-quinoline-3-carbonitrile, 2-[4-(4-F Iuoro-phenyl)-piperazin-1 -yI]-7 ,7-dimethyl-5-oxo-5,6,7, 8-tetrahydro quinoline-3-carbon itri le, 2-(5-m-TolyI-thiazol-2-yI)-7, 8-dihydro-6H-quinolin-5-one, 10 2-[5-(3-Hydroxy-phenyl)-thiazol-2-yU]-7, 8-dihydro-6H-quinolin-5-one, 2-[5-(3-Methoxy-pheny)-thiazo-2-yI]-7,8-dihydro-6H-qiIolin-5-one, 2-[5-(3-Fluoro-ph enyl)-th iazol1-2-yll-7, 8-d ihydro-6H-qu ino lin-5 -one, 2-[5-(3-Chloro-phenyl)-thiazol-2-yIII-7, 8-dihydro-6H-quinolin-5-one, 2-[5-(3-Bromo-phenyl)-thiazol-2-yI-7, 8-dihydro-6H-quinolin-5-one, 15 3-[2-(5-Oxo-5, 67,8-tetrahydro-quinol in-2-yI)-thiazol-5-yI]-benzonitrile, 2-[5-(3,5-D im ethoxy-phenyl)-th iazol-2-yi]-7, 8-dihydro-6H-quinolin-5-one, 2-[2-(3, 5-Dim ethoxy-phenyl)-vinyl-7 ,8-dihydro-6H-quinolin-5-one, 2-[5-(3-Fluoro-5-m ethyl-phenyl)-th iazol-2-yIJ-7, 8-dihydro-6H-quinolin-5-one, 3-Fluoro-5-[2-(5-oxo-5,6,7, 8-tetrahydro-quinolin-2-yI)-thiazol-5-yI] 20 benzonitrile, 2-15-(3-Fluoro-5-m ethoxy-phenyl)-thiazol-2-y]-7 ,8-dihydro-6H-quinolin-5 one, 2-[5-(3-Fluoro-5-pyridin-2-yI-phel)-thiazoI-2-yI]-7, 8-dihydro-6H-quinolin-5 one, 25 2-[5-(3-Fluoro-5-pyridin-3-yI-phel)-th iazol-2-yI]-7 ,8-dihydro-6H-quinol in-5 one, 2-Adamantan-1 -yI-6,7,8,9, 9a, 1 O-hexahydro-5aH-benzo[g]quinolin-5-one, 7, 7-Dimethyl-2-pyridin-3-ylethyl-7, 8-dihydro-6H-quinolin-.5-one, 7, 7-Dimethyl-2-m -olylethynyl-7,8-dihydro-6H-quilolil-5-ofle, 30 2-(3-Hydroxy-phelylethylyl)-7,7-dimlethyl-7, 8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenylethylyl)-7,7-dimethyl-7 ,8-dihydro-6H-quinolin-5-one, 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7 ,8-dihydro-6H -quinolin-5-one, 2-3Clr-hnltyy)77dmthl78dhdo6-unln5oe 2-(3-Bromo-phenylethynYl)-7,7-dimlethyl-7, 8-dihydro-6H-quinolin-5-one, 28 WO 2005/082856 PCT/GB2005/000717 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yIethynyl)-benzonitrile, 7,7-Dimethyl-2-thiazo-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-4-pyridin-3-yl-phenyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 5 one, 2-(3-Methoxy-4-pyridin-2-yl-phenyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-[5-(3-Fluoro-5-pyridin-4-yi-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5 one, 10 2-[5-(3-Fluoro-5-morpholin-4-yi-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin 5-one, 2-[5-(3-Fluoro-5-piperidin-1-yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin 5-one, 7,7-Dimethyl-2-(5-m-tolyl-thiazol-2-yi)-7,8-dihydro-6H-quinolin-5-one, 15 2-[5-(3-Hydroxy-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-[5-(3-Methoxy-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-[5-(3-Fluoro-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 20 one, 2-[5-(3-Chloro-phenyl)-thiazol-2-y]-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-[5-(3-Bromo-phenyl)-thiazol-2-y]-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 25 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-thiazol-5-yl] benzonitrile, 2-[5-(3,5-Dimethoxy-phenyl)-thiazol-2-y]-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one, 2-[2-(3,5-Dimethoxy-phenyl)-vinyl]-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 30 one, 2-[5-(3-Fluoro-5-methyl-phenyl)-thiazol-2-yI]-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one, 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-thiazol-5-yI]-5 fluoro-benzonitrile, 29 WO 2005/082856 PCT/GB2005/00071 7 2-[5-(3-Fuoro-phenyI)-thiazoI-2-yI]-7,8-dihydro-6H-quiflifl-5-one, 2-[5-(3-Fluoro-5-methoxy-phenyl)-thiazol-2-y]-7, 7-dimethyk,8-dihydro-6H quinolin-5-one, 2-[5-(3-Fluoro-5-pyridin-2-yI-phenyl)-thiazol-2-yII-7, 7-dim ethyl-7,8-dihydro 5 6H-quinolin-5-one, 2-[5-(3-Fluoro-5-pyridin-3-yI-phenyl)-thiazol-2-yl]-7, 7-dim ethyl-7, 8-dihydro 6H-quinolin-5-one, 2-[5-(3-Fluoro-5-pyridin-4-yl-phenyl)-th iazol-2-yl]-7, 7-dim ethyl-i, 8-dihydro 6H-quinolin-5-one, 10 2-[5-(3-Fluoro-5-m orpholin-4-yl-phenyl)-thiazol-2-yl]-7,7-dim ethyl-7, 8 dihydro-6H-quinoli6i-5-one, 2-[5-(3-Fluoro-5-p iperidin-1 -yl-phenyl)-thiazol-2-yi]-7, 7-dimethyl-7, 8-dihydro 6H-quinolin-5-one, 2-(5-m-Toly-[1 ,3,4]oxadiazol-2-yl)-7,-dihydro-6H-quilolil-5-ofle, 15 2-(5-m-Tolyl-oxazoI-2-yI)-7,8-dihydro-6H-quilifl-5-ofle, 2-(l -m-TolyI-1 H-imidazol-4-yl)-7,8-dihydro-6H-quinolin-5-ofle, 2-(5-m-Tolyl-isoxazol-3-yl)-7,8-d ihydro-6H-quinol in-5-one, 2-[5-(3-Fluoro-phenyl)-oxazoI-2-yl]-7,8-dihydro-6H-quinolin-5-one, 2-ri -(3-Fluoro-phenyl)-1 H-imidazol-4-yI]-7, 8-dihydro-6H-quinolin-5-one, 20 2-5(-loopey)ioao--y]78dhdo6-unln5oe 3-[2-(5-Oxo-5, 67, 8-tetrahydro-quinolin-2-yI)-oxazoI-5-y]-belzoitrile, 3-[1 -(5-Oxo-5,6,7, 8-tetrahydro-quinolin-2-y)-1 H-imidazol-4-yi]-benzonitrile, 3-[3-(5-Oxo-5, 6,7, 8-tetrahydro-quinolin-2-yl)-isoxazol-5-yl]-belzoflitrile, 3-[2-(7 ,7-Dimethyl-5-oxo-5,6, 7, 8-etrahydro-quinolin-2-y)-oxazol-5-yI] 25 benzonitrile, 3-El -(7,7-Dimethyl-5-oxo-5,6,7, 8-tetrahydro-quinolin-2-y)-1 H-imidazol-4-y] benzonitrile, 3-[3-(7,7-Dimethyl-5-oxo-5 ,6, 7, 8-etrahydro-quinolin-2-yI)-isoxazol-5-yl] benzonitrile, 30 3-[2-(7,7-Dimethyl-5-oxo-5 ,6, 7, 8-etrahydro-qu inolin-2-yl)-oxazol-5-yfl -5 fluoro-benzon itrile, 3-[l1-(7 ,7-Dimethyl-5-oxo-5 ,6, 7, 8-tetrahydro-quinolin-2-y)-1 H-imidazol-4-yl] 5-f Iuoro-benzonitrile, 30 WO 2005/082856 PCT/GB2005/00071 7 3-[3-(7,7-Dim ethyl-5-oxo-5 ,6, 7, 84trahydro-quinolin-2-y)-isoxazol-5-yl]-5 fluoro-benzonitrile, 7,-iehl2(-yii--ihao-2y)78dhdo6-unln5oe 2-(5-Pyridin-3-yI-thiazo-2-yl)-7, 8-dihydro-6H-quinolin-5-one, 5 2-(3-Methoxy-4-pyridin-2-yI-phenylam ino)-7 ,7-dim ethyl-7,8-dihydro-6H quinolin-5-one, 2-(3-Methoxy-4-pyridin-3-yI-phenylam ino)-7 ,7-dim ethyl-7, 8-d ihydro-6H quinolin-5-one, 2-(3-Fluoro-4-pyrid in-2-yl-phenylamino)-7 ,7-dimethyl-7 ,8-dihydro-6H 10 quinolin-5-one, 7,7-Dimethyl-2-(pyridin-2-ylam ino)-7, 8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenylam ino)-7,7-dim ethyl-7,8-dihydro-6H-qu inolin-5-one, 2-Idn2ya io-,-iehl5ox -,,,-erhdoq ioie3 carbonitrile, 15 7,7Dmty -x--heyaio5678ttrhdoqioie3 carbonitrile, 2-(4-Methoxy-phenylam ino)-7,7-dimethyl-5 -oxo-5,6,7, 8-tetrahydro-quinoline 3-carbonitrile, 2-(4-M ethoxy-phenyam ino)-7,7-d im ethyl -3 -n itro-7, 8-dihydro-6 H-q u inol in-5 20 one, 2-(1,3Dh doion o-- -,-ieh l--x -,,,-erh doq ioie 3-carbonitrile, 2-(3,4-Dihydro-1 H-isoquinolin-2-yI)-7, 7-dimethyi-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile, 25 2-(Adamantan-1 -ylamin)77dmty 5oo5678ttahdoqioie3 carbonitrile, 7,7-0 imethyl-3-m orpholin-4-yI-2-(4-phenyl-piperidifl-1 -yI )-7, 8-dihydro-6H quinolin-5-one, [4-(7,7-Dimethyl-5-oxo-5,6, 7, 8-tetrahydro-quinolin-2-ylamilo)-2-methoxy 30 phenyl]-acetonitrile, 2-(3-Fluoro-4-pyridin-3-yi-PhelYlam ino)-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one, [4-(7,7-Dimethyl-5-oxo-5,6,7 ,8-tetrahydro-quinolin-2-yailo)-2-luoro phenyl]-aceton itrile, 31 WO 2005/082856 PCTGB2005OOO717 2-(3-Methoxy-4-pyridin-2-yI-phenyiam ino)-7, 8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-4-pyridin-3-yI-phenylam ino)-7, 8-dihydro-6H-quinolin-5-one, [2-Methoxy-4-(5-oxo-5, 6,7, 8-tetrahydro-quinolin-2-ylam ino)-phenyl] acetonitrile, 5 2-(3-Fluoro-4-pyridin-2-yI-phenylamino)-7,8-dihydro-6H-quilifl-5-one, 2-(3-Fluoro-4-pyridin-3-yI-phenylam ino)-7, 8-dihydro-6H-quinolin-5-one, [2-Fluoro-4-(5-oxo-5, 6,7, 8-tetrahydro-quinolin-2-ylam ino)-phenyl] acetonitrile, 7,7-Dimethyl-2-(pyridin-3-ylam ino)-7, 8-dihydro-6H-quinolin-5-one, 10 7, 7-Dimethyi-2-(pyridin-4-ylamino)-7, 8-dihydro-6H-quinolin-5-one, 5-Oxo-2-(5-phenykthiazo I-2-yI)- 5
,
6 ,7, 8-tetrahydro-quinoline-3-carbonitri le, 2-(3-Methoxy-4-pyridin-2-yI-pheflylam ino)-7, 7-dim ethyl-5-oxo-5, 6,7,8 tetrahydro-quinoline-3-carbonitrile, 2-(3-Methoxy-4-pyridin-3-yI-pheflylam ino)-7, 7-dim ethyl-5-oxo-5,6, 7,8 15 tetrahydro-quinoline-3-carbonitrile, 77 7-Dimethyl-5-oxo-2-(pyridin-4-ylam ino)-5,6,778-tetrahydro-quinoline-3 carbonitrile, 777-0 imethyl-3-n itro-2-(pyridin-4-ylam ino)-7, 8-dihydro-6H-quinolin-5-one, 2-(3,5-Dimethoxy-phenylamino)-7 ,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 20 2-Benzylsulfanyl-7,7-dimethy-3-litro-7,8-dihydro-6H-quilil-5-ofle, 2-B enzylsulfanyl-3-chloro-7 ,7-dimethyl-7,8-dihydro-6H -quinolin-5-one, 777-0 imethyl-3-n itro-2-piperidin- I -yi-7, 8-dihydro-6H-quinol in-5-one, 3-Chloro-7,7-dimethyl-2-piperidifl-1 -yl-7, 8-dihydro-6H-quinolin-5-one, 2-Cyclopentylam ino-7, 7-dimethyl-3-n itro-7,8-dihydro-6H-quinolin-5-one, 25 3-Chloro-2-cyclopentylam ino-7,7-dimethyl-7,8-dihydro-6H-quin olin-5-one, 3-C h oro-2-[4-(4-methoxy-phenyl)-piPerazil- 1 -yi]-7,7-dim ethyl-7,8-dihydro 6H-quinolin-5-one, 2-[4-(4-Methoxy-phenyO)-piperazifl-1 -yi]-7, 7-dimethyf -3-nitro-7, 8-dihydro-6H quinolin-5-one, 30 7,7-0 imethyl-5-oxo-2-(3,4,5,6-tetrahydro-2H-[4,4bipyrdilI -yi)-5, 6778 tetrahydro-quinoline-3-carboflitri le, 2-[4-(4-Methoxy-phel)-piperidifl-1 -yII-7,7-dimethyl-5-oxo-5,6,7, 8 tetrahydro-quinoline-3-carbonitrile, 32 WO 2005/082856 PCT/GB2005/000717 2-[1-(4-Methoxy-phenyl)-piperidin-4-yl]-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile, 7,7-Dimethyl-5-oxo-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino) 5,6 ,7,8-tetrahydro-qu inoline-3-carbonitrile, 5 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-3-nitro-7,8-dihydro-6H-quinolin 5-one, 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-3-nitro-7,8-dihydro-6H-quinolin 5-one, 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 10 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile, 3-[3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-y)-isoxazol-5-y] benzonitrile, 2-Benzylsulfanyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 15 2-(2-Methoxyphenyl)-7,8-dihydro-6H-quinolin-5-one, 2-Benzyloxy-7,8-dihydro-6H-quinolin-5-one, 2-Phenyl-7-7-pentamethylene-7,8-dihydro-6H-quinoline-5-one, 2-(2-Methoxy-phenyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 6-Ethyl-2-phenyl-7,8-dihydro-6H-quinolin-5-one, 20 cis,trans-6-Ethyl-2-(2-m ethoxy-phenyl)-8-m ethyl-7,8-dihydro-6H-quinol in-5 one and cis,trans-8-Ethyl-2-(2-methoxy-phenyl)-6-methyl-7,8-dihydro-6H quinolin-5-one, 6,6,8-Trimethyl-2-phenyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-benzyl)-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one, 25 6-Ethyl-2-(2-methoxy-phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-(2-Methoxy-phenyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 6,6-Dimethyl-2-phenyl-7,8-dihydro-6H-quinolin-5-one hydrochloride, and 2-Benzylsulfanyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3 carbonitrile 30 DETAILED DESCRIPTION OF THE INVENTION [0035] For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the 33 WO 2005/082856 PCT/GB2005/000717 prefix Ci.; indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, (CI- 3 )alkyl refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof. 5 [0036] As used herein and as far as it is not defined in a different manner elsewhere in this description or the accompanied claims , the term "C 1
.
6 alkyl" represents straight or branched chain alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms; the term 10 "C 2
.
6 alkenyl" represents straight or branched chain alkenyl groups having 2, 3, 4, 5 or 6 carbon atoms; the term "cycloC 3
-
12 alkyl" represents monocyclic or bicyclic, or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantanyl; the term "aryl" represents phenyl or 15 naphthyl, or phenyl substituted by one or more substituents selected independently from a halogen, trifluoromethyl,
C
1
.
6 alkyl, C 2
.
6 alkenyl, C 1
.
6 alkoxy, amino, hydroxy, nitro, cyano, C 1 . 6 alkoxycarbonyl, C1- 6 alkylamino, di-C 1 -6alkylamino, piperidinyl, morpholinyl, and pyridyl; the term "biaryl" represents biphenylene, preferably 4,4' 20 biphenylene, wherein one or both phenyl rings may optionally be substituted independently by one or more of the substituents independently selected from a halogen, trifluoromethyl, C 1
.
6 alkyl,
C
2
-
6 alkenyl, C 1
.
6 alkoxy, amino, hydroxy, nitro, cyano, C1.
6 alkoxycarbonyl,
C
1
.
6 alkylamino, di-C 1
.
6 alkylamino, piperidinyl, morpholinyl, and pyridyl; the 25 term "heteroaryl" represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a 5-6 membered bicyclic ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and 30 nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents selected independently from a halogen, trifluoromethyl, C1.
6 alkyl, C 2
-
6 alkenyl, C 1
.
6 alkoxy, amino, hydroxy, nitro, cyano, C 1
.
6 alkoxycarbonyl, C 1 .salkylamino, di-C 1
.
6 alkylamino, piperidinyl, morpholinyl, pyridyl, and aryl; heteroaryl may be furyl, thiophenyl, pyrrolyl, oxazolyl, 34 WO 2005/082856 PCT/GB2005/000717 isoxazolyl, thiazolyl, imidazolyl, tetrazolyl, pyridinyl, pyrimidyl, benzofuryl, benzothiophenyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl and isoquinolyl; and the term "halogen" represents fluorine, chlorine, bromine and iodine. 5 (0037] The compounds of the present invention are named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl, "Et" for ethyl, "h" for hour or hours, and "rt" for room temperature). 10 [0038] The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 1-aminocyclohexane), but has been modified in a targeted and controlled manner to replace one or more specific 15 substituents of the referent molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule. Synthesis and screening of analogs (e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher 20 potency and/or selectivity at a specific targeted receptor type, greater ability to penetrate mammalian blood-brain barriers, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry. [0039] In addition, using methods known to those skilled in the art, analogs 25 and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy in controlling dementia, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc. 30 [0040] The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal 35 WO 2005/082856 PCT/GB2005/000717 (e.g., human). Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in 5 humans. [0041] Compounds of the present invention may be in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to those salts which possess the biological effectiveness and 10 properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity. 15 [0042] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention ecompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture 20 thereof, of a compound of the invention, which possesses the useful properties described herein. [0043] The following Schemes 1-2 describe the preparation of compounds of Formula IA of the present invention. All of the starting materials are 25 prepared by procedures described in these schemes, by procedures well known to one of ordinary skill in organic chemistry or can be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in 30 organic chemistry. All of the variables used in the schemes are as defined below or as in the claims. [0044] Compounds of general Formula IA were obtained, as shown in Scheme 1, by reacting appropriately functionalized cyclohexane-1,3-dione 36 WO 2005/082856 PCT/GB2005/000717 derivatives 1 with N,N-dimethylformamide dimethyl acetal and, subsequently, 2-cyano-thioacetamide to form the corresponding 5-oxo-2 thioxo-1,2,5,6,7,8-hexahydro-quinoline-3-carbonitrile derivative 3. Alkylation of 3 with alkyl halides under basic conditions led to 2-alkylsulfanyl-5-oxo 5 5,6,7,8-tetrahydro-quinoline-3-carbonitriles of Formula IA. The introduction of an amino-substituent was achieved by reacting 2-methylsulfanyl-5-oxo 5,6,7,8-tetrahydro-quinoline-3-carbonitriles 4 with a primary or secondary amine derivative to give amino substituted derivatives of Formula IA. 37 WO 2005/082856 PCT/GB2005/000717 Scheme I Synthesis of 3-cyano-substituted 7,8-d ihydro-6H-quinolin-5 ones R OR
R
8 R NaOR 11 R I A
R
5 3 HO ~ 2 N 'R -B-R 2R 7 6 R7 IHO' R 7 R 8 N R R8R9RiNCI R R9 R 1 0 7 (R 3 =CN) HNRlIR 12 I A R 5 0 N R 5 0 6 R6 ' N
-
8 N N ",NXRR9
R
10 12 R 9 10 H 3CX =0) H 2 N 0 I A R 0 5R 0e 6Me NCH(OMe) 2 6SN Me N
RZ
7 RM7N' H2e 8 QR 7 1 R 0 0 R R 9 10 RR R 1 1 2 R 5 0 N R 5 0 'N R 11 HaI R 8 ' R R 7 I R ' 0 R ~1 M [ 3 (X S) .IA R 7 R 'NR MeN-N 8 N S'
R
9 10N R R 9R 1 RR '12 4 IA 38 WO 2005/082856 PCT/GB2005/000717 [0045] A synthetic procedure toward 3-unsubstituted 7,8-dihydro-6H quinolin-5-ones with the general Formula IA is given in Scheme 2. The reaction of appropriately functionalized cyclohexane-1,3-dione derivatives 1 5 with ammonium acetate / acetic acid in benzene gave the corresponding 3 amino-cyclohex-2-enone derivatives 5. Compound 5 was then reacted with ethyl propiolate and cyclization was achieved at elevated temperatures to form the quinoline-2,5-dione 6. Subsequent reaction with phosphoryl chloride gave the 2-chloro-substituted quinolin-5-one derivative 7. 10 Substitution of the chloro-substituent with either alkoxide or a primary amine yielded compounds of Formula IA bearing an amino or ether linker. Alternatively, compound 5 can also be treated with appropriately functionalized propenones in the presence of Pd/C to give additional 3 unsubstituted compounds corresponding to the general Formula IA. 15 39 WO 2005/082856 PCT/GB2005/000717 Scheme 2 Synthesis of 3-unsubstituted 7,8-dihydro-6H-quinolin-5-ones 0 R 5 0 R 5 0 AlkylI 5 0
R
6 NH 40Ac N O ON
R
7 )0. R 6 0 13 NHN 0 RR 10
''RZ
9
R
1 0 2 N\R R 1 0 1 56 R2 POC1 3 OH or R O
R
1 Hal S RR a 7 'N-C R R9 R 10 HO NaOR HO ' 7 (R 3 = H) 6 6 RRZ7 IR R 2 8 1 N 0' N RR101R A [A R 5 E RP 5 R 6 6
R
7 I . R 11 7 R 9 IN N' R 8 R9 R 10 N R R ~12RR I 1A 1A 5 [00461 It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry. 10 EXPERIMENTAL PART [0047] The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are 40 WO 2005/082856 PCT/GB2005/000717 intended as an illustration of and not a limitation upon the scope of the invention. [0048] Hereinafter, "DMF" is defined as N,N-dimethylformamide, "HCI" as 5 hydrochloric acid, "DMSO" as dimethylsulfoxide and "TMS" as tetramethylsilane. Preparation I 7,7-Dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3 10 carbonitrile 0 N S H [0049] The title compound was obtained according to (Abu-Shanab, F. A.; Redhouse, A. D.; Thompson, J. R.; Wakefield, B. J. Synthesis. 1995, 557.) as a yellow solid in 52% yield. 15 Preparation 2 5-Oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3 -carbonitrile 0 N S H [0050] Prepared in 52% yield from cyclohexane-1,3-dione in analogy to the 20 procedure described for 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8 hexahydroquinoline-3-carbonitrile synthesis. 41 WO 2005/082856 PCT/GB2005/000717 Preparation 3 7,7-Dimethyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydroquinoline -3 carbonitrile 0 N SN 5 [0051] In analogy to the procedure described in Example 1, 7,7-dimethyl-5 oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with lodomethane to give the title compound in 89% yield. Physical characteristics are as follows: 'H NMR (CDC1 3 , T/IMS) 5: 1.12, 2.54, 2.68, 3.03, 8.32. 10 Preparation 4 3-Amino-5,5-dimethylcyclohex-2-en-1 -one 0 /
NH
2 [0052]The title compound was prepared according to (Baraldi, P. G.; 15 Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903.) as a colorless solid in 76% yield. Preparation 5 7,7-Dimethyl-7,8-dihydro-1H,6H -quinoline-2,5-dione 0 N 0 20 H [0053] In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092.), 3-amino-5,5-dimethylcyclohex-2-en-1-one was reacted with ethyl propio-late to give the title compound as a light brown solid in 78.5% yield. 25 Physical characteristics are as follows: 1 H NMR (CDC 3 , TMS) 5: 1.14, 2.42, 2.82, 6.47, and 8.04. 42 WO 2005/082856 PCT/GB2005/000717 Preparation 6 2-Chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 NCI 5 [0054] In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsik. Soedin. 1991, (1) 86-92.) 7,7-dimethyl-7,8 dihydro-1H,6H-quinoline-2,5-dione was treated with phosphoryl chloride
(POC
3 ) to give the title compound as a gray solid in 60% yield. Physical characteristics are as follows: 10 'H NMR (CDC 3 , TMS) 6: 1.11, 2.54, 3.01, 7.30, and 8.30. Preparation 7 3-Amino-5-ethylcyclohex-2-en-1-one 0
NH
2 15 [0055] In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-ethylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound. Physical characteristics are as follows: 20 'H NMR (CDC1 3 , TMS) 8: 0.93 (t, 6.5 Hz, 3H); 1.42 (m, 2H); 1.88 - 2.44 (m, 5H); 4.62 (br s, 2H) and 5.23 ppm (s, 1 H). Preparation 8 3-Amino-6-propylcyclohex-2-en-1-one 0 25 NH 2 43 WO 2005/082856 PCT/GB2005/000717 [0056] In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4-propylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: 5 'H NMR (CDC13, TMS) 5: 0.91 (t, 7 Hz, 3H); 1.25 - 1.90 (m, 5H); 1.98 - 2.18 (m, 2H); 2.35 (t, 6 Hz, 2H); 4.50 (br s, 2H) and 5.19 ppm (s, 1H). Preparation 9 3-Amino-5-isopropylcyclohex-2-en-1 -one 0 10
NH
2 [0057] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-isopropylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid. 15 Physical characteristics are as follows: 'H NMR (CDCl3, TMS) 6: 0.91 (d, 6.5 Hz); 1.48 - 1.65 (m, 1H); 1.84 - 2.39 (m, 5H); 5.04 (br s, 2H) and 5.22 ppm (s, 1H). Preparation 10 20 3-Amino-6,6-dimethylcyclohex-2-en-1 -one 0
NH
2 [0058] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4,4-dimethylcyclohexane-1,3-dione was reacted with 25 ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: Mp 153-154 -*C; 1H NMR (DMSO-D6, TMS) 6: 0.94 (s, 6H); 1.64 (t, 6.5 Hz, 2H); 2.28 (t, 6.5 Hz, 2H); 4.79 (s, 1 H) and 6.58 ppm (br s, 2H). 44 WO 2005/082856 PCT/GB2005/000717 Preparation 11 3-Amino-6-ethyl-6-methylcyclohex-2-en-1 -one 0
NH
2 5 [0059] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4-ethyl-4-methylcyclohexane-1,3-dione was reacted with ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: 10 -'H NMR (CDCl3, TMS) 5: 0.83 (t, 6.5 Hz, 3H); 1.06 (s, 3H); 1.40 - 1.80 (m, 3H); 1.85 - 2.00 (m, 1H); 2.35 (t, 6.5 Hz, 2H); 4.31 (br s, 2H) and 5.14 ppm (s, 1H). Preparation 12 15 3-Amino-5-phenylcyclohex-2-en-1 -one 0
NH
2 [0060] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-phenylcyclohexane-1,3-dione was reacted with 20 ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: 'H NMR (CDC 3 , TMS) 5: 2.40 - 2.75 (m, 4H); 3.28 - 3.45 (m, 1 H); 4.58 (br s, 2H); 5.34 (s, I H) and 7.23 - 7.42 ppm (m, 5H). 25 Preparation 13 3-Amino-4,6,6-trimethylcyclohex-2-en-1 -one 45 WO 2005/082856 PCT/GB2005/000717 0
NH
2 [0061] In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 4,4,6-trimethylcyclohexane-1, 3-dione was 5 reacted with ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: -1H NMR (CDCl3, TMS) 6: 1.10 (s, 6H); 1.20 (d, 6 Hz, 3H); 1.60 - 1.79 (m, 2H); 2.60 - 2.80 (mn, I H); 4.60 (br s, 2H) and 5.10 ppm (s, 1 H). 10 Preparation 14 7-Phenyl-7,8-dihydro-1 H,6H-quinoline-2,5-dione 0 N O H [0062] In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 15 1968, 33 (3) 1089-1092.), 3-amino-5-phenylcyclohex-2-en-1-one reacted with ethyl propiolate to give the title compound as a colorless solid. Physical characteristics are as follows: Mp 273-274 0 C; 'H NMR (CDC1 3 , TMS) 5: 2.68 - 3.95 (m, 2H); 3.17 (d, 8 Hz, 2H); 3.40 - 3.60 (m, IH); 6.46 (d, 9 Hz, IH); 7.25 - 7.42 (m, 5H) and 8.07 20 ppm (d, 9 Hz, IH); Anal. Found (C 15
H
13
NO
2 ) (%): C, 74.9; H, 5.5; N, 5.8. Preparation 15 2-Chloro-7-phenyl-7,8-dihydro-6H-quinolin-5-one 46 WO 2005/082856 PCT/GB2005/000717 0 N Ci [0063] In analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsikl. Soedin. 1991, (1) 86-92.) 7-phenyl-7,8 dihydro-1H,6H-quinoline-2,5-dione was treated with phosphoryl chloride 5 (POCl 3 ) to give after chromatographical separation the title compound as a colorless solid. Physical characteristics are as follows: 'H NMR (CDCl 3 , TMS) 5: 2.80-3.00 (m, 2H); 3.20-3.60 (m, 3H); 7.25-7.45 (m, 6H); 8.27 ppm (d, 8 Hz, 1H). 10 Preparation 16 3-Amino-5-(4-dimethylamino-phnyl)-cyclohex- 2 -en-I -one 0 NH2 N 15 [0064] In close analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) 5-(4-dimethylamino-pheny)-cyclohexane-1,3 dione was reacted with ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: 20 1 H NMR (CDCI3, TMS) 5: 2.35 - 2.70 (m, 4H); 2.93 (s, 6H); 3.18 - 3.34 (m, 1H); 4.77 (br s, 2H); 5.32 (1s, H); 6.71 (d, 9 Hz, 2H) and 7.12 ppm (d, 9 Hz, 2H). Preparation 17 25 9-Amino-spiro[4.5]dec-8-en-7-one 47 WO 2005/082856 PCT/GB2005/000717 0
NH
2 [0065] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) spiro[4.5]decane-7,9-dione was reacted with ammonium 5 acetate to give the title compound as a colorless solid. Physical characteristics are as follows: 'H NMR (CDCl3, TMS) 5: 1.45 - 1.70 (m, 8H); 2.25 (s, 2H); 2.28 (s, 2H); 4.61 (br s, 2H) and,5.22 ppm (s, 1 H). 10 Preparation 18 4-Amino-spiro[5.5]undec-3-en-2-one 0
NH
2 [0066] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 15 1983, (11) 902-903) spiro[5.5]undecane-2,4-dione was reacted with ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: 'H NMR (CDCI3, TMS) 5: 1.46 - 1.68 (m, 8H); 2.25 (s, 2H); 2.28 (m, 1H); 4.61 (br s, 2H) and 5.22 ppm (s, 1 H). 20 Preparation 19 7,7-Pentamethyene-7,8-dihydro-1 H,6H-quinoline-2,5-dione 0 N 0 H 48 WO 2005/082856 PCT/GB2005/000717 [0067] In analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092.), 4-amino-spiro[5.5]undec-3-en-2-one reacted with ethyl propiolate to give the title compound as a colorless solid. Physical characteristics are as follows: 5 Mp 273-274 0 C; 'H NMR (CDCI 3 , TMS) 5: 1.49 (m, 10H); 2.52 (s, 2H); 2.84 (s, 2H); 6.47 (d, 9 Hz, 1H); 8.01 (d, 9 Hz, 1H) and 12.80 ppm (br s, IH); Anal. Found (C 14
H
17
NO
2 ) (%): C, 72.1; H, 7.4; N, 5.9. Preparation 20 10 3-Amino-4a,5,6,7,8,8a-hexahydro-4H-naphthalen-1-one 0 NH2 [0068] In analogy to (Baraldi, P. G.; Simoni, D.; Manfredini, S.; Synthesis 1983, (11) 902-903) hexahydro-naphthalene-1,3-dione (prepared from 1 15 cyclohex-1 -enyl-ethanone according to (Chuang; Tien. Chem. Ber. 1936; 69; 25-29) was reacted with ammonium acetate to give the title compound as a colorless solid. Physical characteristics are as follows: Mp 208-210 *C; 'H NMR (DMSO-De, TMS) 5: 0.75-1.35 (m, 4H); 1.4-1.9 (m, 20 5H); 1.9-2.3 (m, 3H); 4.88 (s, I H); 6.43 (br s, 2H). Preparation 21 6,7,8,9,9a,10-Hexahydro-1H,5aH-benzo[g]quinoline-2,5-dione 0 C NO H 25 [0069] In close analogy to (Pettit, G. R.; Fleming, W. C.; Paull, K. D. J. Org. Chem. 1968, 33 (3) 1089-1092.), 3-amino-4a,5,6,7,8,8a-hexahydro-4H 49 WO 2005/082856 PCT/GB2005/000717 naphthalen-1-one was reacted with methyl propiolate to give the title compound as a colorless solid. Physical characteristics are as follows: Mp 301-303 *C; 'H NMR (DMSO-D,, TMS) 6: 1.0-1.3 (m, 4H); 1.6-1.65 (m, 5 4H); 2.04 (dt, IH); 2.17 (d, 1H); 2.62-2.72 (m, 2H); 6.21 (d, 1H); 7.73 (d, 1H); 11.92 (br s, IH). Preparation 22 2-Chloro-2,5a,6,7,8,9,9a,1 0-octahydro-1 H-benzo[g]quinolin-5 -one 0 10 [00701 In close analogy to (Shanazarov, A. K.; Kuzovkin, V. A.; Chistjakov, V. V.; Granik, V. G. Khim. Geterotsik. Soedin. 1991, (1) 86-92.) 6,7,8,9,9a,10-hexahydro-1H,5aH-benzo[g]quinoline-2,5-dione was treated with phosphoryl chloride (POCi 3 ) to give after chromatographical separation 15 the title compound as a colorless solid. Physical characteristics are as follows: Mp 111-113 *C; 'H NMR (DMSO-D 6 , TMS) 6: 1.10-1.35 (m, 4H); 1.65-1.92 (m, 4H); 2.20 (d, IH); 2.33 (dt, IH); 2.85-3.00 (m, 2H); 7.47 (d, IH); 8.14 (d, 1H). MS 236 (M+1). 20 Example I 2-Butylsulfanyl-7,7-dimethyl -5-oxo-5,6,7,8-tetrahydroquinoline-3 carbonitrile 0 I N' 25 [0071] To a solution of 7,7-dimethy-5-oxo-2-thioxo-1,2,5,6,7,8 hexahydroquinoline-3-carbonitrile (0.5 g, 2.2 mmol) in DMF (4 ml) was added 10 % aqueous potassium hydroxide (1.23 ml), followed by dropwise addition of 1-bromobutane (0.24 ml, 2.2 mmol). The mixture was stirred at 50 WO 2005/082856 PCT/GB2005/000717 room temperature for 12 h, then water (12 ml) was added. The product was extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate. Filtration and concentration under reduced pressure afforded the residue which was purified by flash chromatography on silica 5 gel (petroleum ether - ethyl acetate, 10:1) to give the title compound (0.41 g, 59%) as a colorless solid. Physical characteristics are as follows: Mp 50-52 "C; 'H NMR (CDC13, TMS) 5: 0.97, 1.12, 1.49, 1.74, 2.53, 3.01, 3.32, and 8.31; Anal. Found (C1 6
H
2 oN 2 OS*1.5H20) (%): C, 61.0; H, 7.0; N, 10 8.5. Example 2 7,7-Dimethyl-5-oxo-2-propylsulfanyl-5,6,7,8-tetrahydroquinoline-3 carbonitrile 0 15 ' N S [0072] In analogy to the procedure described in Example 1, 7,7-dimethyl-5 oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 1 -bromopropane to give the title compound in 91% yield. Physical characteristics are as follows: 20 Mp 100-102 0 C; 'H NMR (CDCl 3 , TMS) 5: 1.07, 1.12, 1.78, 2.53, 3.01, 3.30, and 8.31; Anal. Found (C 15 H13N 2 0S) (%): C, 65.7; H,_6.6; N, 10.2. Example 3 2-IsopropyIsulfanyl-7,7-dimethyl -5-oxo-5,6,7,8-tetrahydroquinoline-3 25 carbonitrile 0 [0073] In analogy to the procedure described in Example 1, 7,7-dimethyl-5 oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 2-bromopropane to give the title compound in 21% yield. 51 WO 2005/082856 PCT/GB2005/000717 Physical characteristics are as follows: Mp 135-136 0C; 'H NMR (CDCl 3 , TMS) 5: 1.12, 1.46, 2.53, 3.01, 4.20, and 8.31; Anal. Found (C 15 HisN 2 0S) (%): C, 65.5; H, 6.7; N, 9.8. 5 Example 4 7,7-Dimethyl-2-(2-methylallyisulfanyl)-5-oxo-5,6,7,8 tetrahydroqu inoline-3 -carbon itrile 0 / N S [00741 In analogy to the procedure described in Example 1, 7,7-dimethyl-5 10 oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 3-chloro-2-methylpropene to give the title compound in 21% yield. Physical characteristics are as follows: Mp 78-79 *C. 'H NMR (CDC13, TMS) 6: 1.12, 1.86, 2.54, 3.01, 4.02, 4.93, 5.10, and 8.32; Anal. Found (C 1 sH 18
N
2 0S) (%): C, 67.1; H, 6.3; N, 9.8. 15 Example 5 2- sobutyisulfanyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3 carbonitrile 0 N N 20 [0075] In analogy to the procedure described in Example 1, 7,7-dimethyl-5 oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 1-bromo-2-methylpropane to give the title compound in 42% yield. Physical characteristics are as follows: Mp 75-76 'C; 'H NMR (CDC1s, TMS) 5: 1.07, 1.12, 2.00, 2.52, 2.99, 3.23, 25 and 8.31; Anal. Found (C 16
H
20
N
2 0S) (%): C, 66.5; H, 7.0; N, 9.7. 52 WO 2005/082856 PCT/GB2005/000717 Example 6 2-(2-M ethylallylsulfanyl) -5-oxo-5,6,7,8-tetrahydroquinoline- 3 carbonitrile 0 N N S 5 [0076] In analogy to the procedure described in Example 1, 5-oxo-2-thioxo 1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 3-chloro-2 methylpropene to give the title compound in 89% yield. Physical characteristics are as follows: Mp 85-86 *C; 1 H NMR (CDC1 3 , TMS) 5: 1.85, 2.19, 2.68, 3.12, 4.00, 4.92, 10 5.10, 8.34; Anal. Found (C 1 14 1N 2 0S) (%): C, 64.8; H, 5.5; N, 10.8. Example 7 7,7-Dimethyl-5-oxo-2-piperidin -1 -yl -5,6,7,8-tetrahydro-quinolin e-3 carbonitrile 0 15 N 'NJ 15 [0077] A solution of 7,7-dimethyl-2-methylsulfanyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile (0.25 g, 1 mmol) and piperidine (0.32 ml, 4 mmol) in dry ethanol (3 ml) was stirred at reflux for 36 h. The reaction mixture was then evaporated under reduced pressure. The residue was purified by flash 20 chromatography on silica gel (chloroform - methanol, 50:1) to give the title compound (0.08 g, 28%) as a colorless solid. Physical characteristics are as follows: Mp 99-100 0C; 'H NMR (CDCl 3 , TMS) 5: 1.08, 1.73, 2.45, 2.79, 3.91, and 8.33; Anal. Found (C 17
H
21
N
3 0) (%): C, 71.6; H, 7.5; N, 14.4. 25 53 WO 2005/082856 PCT/GB2005/000717 Example 8 2-Benzylamino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3 carbonitrile hydrochloride 0 H -HCI N'N H 5 [0078] A solution of 7,7-dimethyl-2-methylsulfanyl-5-oxo-5,6,7,8 tetrahydroquinoline-3-carbonitrile (0.25 g, 1 mmol), benzylamine (0.13 g, 1.2 mmol) and sodium acetate (0.41 g, 3 mmol) in dry ethanol (3 ml) was stirred at reflux for 60 h. The reaction mixture was then evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel 10 (chloroform - methanol, 30:1) and treated with a dry HCI solution in diethyl ether to give the title compound (0.072 g, 21 %) as a colorless solid. Physical characteristics are as follows: Mp 163-164 *C; 1 H NMR (CDCI 3 , TMS) 8: 1.11, 2.48, 2.95, 4.88, 7.38, and 8.38; Anal. Found (C1 9 Hl9N 3 0*HCI) (%): C, 66.7; H, 5.9; N, 12.3. 15 Example 9 2-Cyclohexyloxy-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 HC N' 07 20 [0079] To a solution of cyclohexanol (0.2 g, 2.0 mmol) in diethyl ether (10 ml) was added sodium (0.035 g, 1.5 mmol) and it was stirred at room temperature for 2.5 h. Then 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one (0.21 g, 1.0 mmol) was added and the resulting mixture was stirred at 30 *C for 24 h. Water (12 ml) was added and the mixture was extracted with 25 ethyl acetate (2x10 ml). The organic phase was washed with water (10 ml) and dried over magnesium sulphate, then it was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether - ethyl acetate, 10:1) followed by treatment 54 WO 2005/082856 PCT/GB2005/000717 with a dry 0.5M HCI solution in diethyl ether to give the title compound (0.28 g, 47%) as a colorless solid. Physical characteristics are as follows: Mp 126-127 CC; 1 H NMR (CDC1 3 , TMS) 5: 1.14, 1.3-2.1, 2.53, 3.45, 5.1-5.3, 5 6.96, and 8.53; Anal. Found (C 7
H
23
NO
2 *HCI*0.5H20) (%): C, 64.4; H, 7.5; N, 4.4. Example 10 2-isobutoxy-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 HC1 10 [0080] In analogy to the procedure described in Example 9, 2-chloro-7,7 dimethyl-7,8-dihydro-6H-quinolin-5-one was treated with iso-butyl alcohol to give the title compound in 35% yield. Physical characteristics are as follows: 15 Mp 157-158 0C; 'H NMR (CDCl 3 , TMS)5: 1.12, 1.15, 2.28, 2.56, 3.52, 4.32, 7.06, 8.64, and 9.0 - 9.5; Anal. Found (C 15
H
21
NO
2 * HCI) (%): C, 64.0; H, 7.8; N, 4.9. Example 11 20 2-Benzyloxy-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 OHCI 4 [1:N 0 [0081] In analogy to the procedure described in Example 9, 2-chloro-7,7 dim ethyl-7,8-dihydro-6H-quinolin-5-one was treated with benzyl alcohol to give the title compound in 33% yield. 25 Physical characteristics are as follows: 55 WO 2005/082856 PCT/GB2005/000717 Mp 87-88 *C; 'H NMR (CDCl 3 , TMS) 5: 1.15, 2.55, 3.50, 5.70, 7.07, 7.30 7.60, and 8.58; Anal. Found (C 1 8
H
19 N0 2 * HCI * 0.33 H 2 0): C, 66.8; H, 6.2; N, 4.5. 5 Example 12 2-Benzylamino-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 -one hydrochloride 0 HCI N' N H [0082] 2-Chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one (0.315 g, 1.5 10 mmol) and potassium carbonate (0.83 g, 6 mmol) were added to a solution of benzylamine (0.2 g, 1.8 mmol) in dry acetonitrile (4 mi). The mixture was stirred at reflux for 48 h. DMSO (3 ml) and sodium hydride (0.05 g) were added and heating was continued for additional 5 h. Water (10 ml) was added and the mixture was extracted with chloroform (2x10 ml). The extract 15 was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (chloroform - methyl alcohol, 40:1), then treated by dry HCI in diethyl ether to give the title compound (0.1 g, 21%) as a colorless solid. Physical characteristics are as follows: 20 Mp 215-216 *C; 'H NMR (CDC 3 , TMS) : 1.14, 2.48, 3.08, 4.60, 6.64, 7.3 7.4, 8.23, and 9.67; Anal. Found (CieH 2 oN 2 0*HCl) (%): C, 68.4; H, 6.7; N, 8.5. Example 13 25 7,7-Dimethyl-2-phenethyl-7,8-dihydro-6H-quinolin-5-one hydrochloride HCI 'N 56 WO 2005/082856 PCT/GB2005/000717 [0083] A mixture of 4 A molecular sieves (140 mg), 5-phenylpent-1-en-3-one (Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J.; SynLett. 1997, (12) 1414-1416.) (0.22 g, 1.4 mmol), 3-amino-5,5-dimethylcyclohex-2-en-1-one, and 10% Pd/C (14 mg) in toluene (4 ml) was heated at reflux for 4.5 h. It 5 was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (chloroform methanol, 30 : 1), then it was treated by a dry HCI solution in diethyl ether to give the title compound (0.2 g, 45%) as a colorless solid. Physical characteristics are as follows 10 Mp 173-175 "C; 'H NMR (CDCl 3 , TMS) 6: 1.18, 2.63, 3.24, 3.62, 3.70, 7.15 7.30, 7.37, and 8.61; Anal. Found (CigH 2 1NO*HCI) (%): C, 71.6; H, 7.0; N, 4.4. Example 14 15 2-Benzyl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 HC 1 N [0084] In analogy to the procedure described in Example 13, 3-amino-5,5 dimethylcyclohex-2-en-1 -one was reacted with I-phenylbut-3-en-2-one (prepared in analogy to Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J.; 20 SynLett. 1997, (12) 1414-1416.) to give the title compound in 33% yield. Physical characteristics are as follows: Mp 202-204 0C; 'H NMR (CDCl 3 , TMS) 6: 1.19, 2.63, 3.65, 4.80, 7.30 - 7.45, 7.45, and 8.64; Anal. Found (Cl 8 HigNO*HCI) (%): C, 70.9; H, 6.7; N, 4.3. 57 WO 2005/082856 PCT/GB2005/000717 Example 15 2-Benzyl-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 HCI CN [0085] In analogy to the procedure described in Example 13, 3 5 aminocyclohex-2-en-1 -one was reacted with I-phenylbut-3-en-2-one to give the title compound in 50% yield. Physical characteristics are as follows: Mp 185-187 *C; 'H NMR (CDC 3 , TMS) 5: 2.30 (m, 2H); 2.78 (t, 6.5 Hz, 2H); 3.76 (t, 6.0 Hz, 2H); 4.75 (s, 2H); 7.20 - 7.50 (m, 5H); 7.50 (d, 8.0 Hz, 1 H) 10 and 8.65 ppm (d, 8.0 Hz, 1H); Anal. Found (Cl 6
H
15 NO*HCI): (%) C, 70.3; H, 5.9; N, 5.1. Example 16 2-Phenethyl-7,8-dihydro-6H-quilnoliln-5-one hydrochloride 0 N -*HCI
'N
15 [0086]ln analogy to the procedure described in Example 13, 3 aminocyclohex-2-en-1 -one was reacted with 5-phenylpent-1-en-3-one to give the title compound in 33% yield. Physical characteristics are as follows: 20 Mp 200 *C (dec.); 'H NMR (CDCl 3 , TMS) 5: 2.10 - 2.40 (m, 2H); 2.79 (t, 6.6 Hz, 2H); 3.24 (t, 7.4 Hz, 2H); 3.60 - 3.80 (m, 4H); 7.20 - 7.40 (m, 5H); 7.35 (d, 9.0 Hz, I H) and 8.62 ppm (d, 7.8 Hz, I H); Anal. Found (CgH 2 1NO*HCI*0.5H 2 0): (%) C, 68.9; H, 6.2; N, 4.5. 25 Example 17 2-[2-(2-Methoxyphenyl)ethyl]-7,8-dihydro-6H-quinolin-5-one hydrochloride 58 WO 2005/082856 PCT/GB2005/000717 -HCl' [0087] In analogy to the procedure described in Example 13, 3 aminocyclohex-2-en-1 -one was reacted with 5-(2-methoxyphenyl)pent-1-en 3-one (prepared in analogy to Martin, R.; Romea, P.; Tey, C.; Urpi, F.; 5 Vilarrasa, J.; SynLett. 1997, (12) 1414-1416.) to give the title compound in 33% yield. Physical characteristics are as follows: Mp 160-162 OC; 'H NMR (CDCl 3 , TMS) 5: 2.29, 2.79, 3.22, 3.66, 3.76, 3.78, 6.84, 7.16, 7.32, and 8.59; Anal. Found (C 16
H
1 9
NO
2 *HCI): (%) C, 67.7; H, 10 6.3; N, 4.2. Example 18 7,7-Dimethyl-2-styryl-7,8-dihydro-6H-quinolin-5 -one hydrochloride - HCI 15 [0088] In analogy to the procedure described in Example 13, 3-amino-5,5 dim ethylcyclohex-2-en-1 -one was reacted with I-phenylpenta-1,4-dien-3 one (prepared in analogy to Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J.; SynLett. 1997, (12) 1414-1416.) to give the title compound in 20 19% yield. Physical characteristics are as follows: Mp 218-220 'C; 'H NMR (CDCla, TMS) 6: 1.06, 2.58, 3.08, 7.49, 7.30 - 7.55, 7.70 - 7.80, 7.75, 7.92, and 8.28; Anal. Found (CiaHigNO*HCI*0.33H 2 0): C, 71.4; H, 6.5; N, 4.2. 25 59 WO 2005/082856 PCT/GB2005/000717 Example 19 2-(Adamantan-1 -yI)-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 - HCI N [0089] In analogy to the procedure described in Example 13, 3 5 aminocyclohex-2-en-1 -one was reacted with 1-adamantan-1-yl-propenone (Stepanow, F. N.; Myrsina, R. A. J. Org. Chem. USSR (Engl. Transl.) 1966, 2, 644-647; Zh. Orp. Khim. 1966, 2 (4) 644-648.) to give the title compound in 12% yield. Physical characteristics are as follows: 10 Mp 214-216 *C; 'H NMR (CDCl 3 , TMS) 6: 1.80, 1.93, 2.10 - 2.45,2.78,4.05, 7.67, and 8.78; Anal. Found (Cj9H 23 NO*HCl): (%) C, 71.5; H, 7.6; N, 4.3. Example 20 2-(Adamantan-1 -y)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 15 hydrochloride 0 N [0090] In analogy to the procedure described in Example 13, 3-amino-5,5 dim ethylcyclohex-2-en-1 -one was reacted with I -adamantan-1-yl-propenone to give the title compound in 32% yield. 20 Physical characteristics are as follows: Mp 210-212 *C; Anal. Found (C 21
H
27 NO*1.5HCI): (%) C, 69.3; H, 7.9; N, 3.7. 'H NMR (CDCl3, TMS) 5: 1.18, 1.79, 1.93, 2.23, 2.37, 2.62, 3.90, 7.68, and 8.76. 25 Example 21 2-Adamantan -1 -yl -6-propyl -7,8-dihydro-6H -qui nolin -5-one 60 WO 2005/082856 PCT/GB2005/000717 0
H
3 C [0091] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 22 2-Benzyloxy-7-(4-chloro-phenyl)-7,8-dihydro-6H-quinolin-5-one 0 N O [0092] In analogy to the procedure described in Example 9, the title 10 compound is obtained in significant yield. Example 23 2-Isobutoxy-7-phenyl-7,8-dhydro-6H-quinolin-5-one 0 HCl N O 15 [00931 In analogy to the procedure described in Example 8, 2-chloro-7,7 dimethyl-7,8-dihydro-6H-quinolin-5-one was treated with iso-butyl alcohol to give the title compound in 35% yield. Physical characteristics are as follows: Mp 157-158 *C; 1 H NMR (CDCl 3 , TMS)5: 1.12, 1.15, 2.28, 2.56, 3.52, 4.32, 20 7.06, 8.64, and 9.0 - 9.5; Anal. Found (C 15
H
21
NO
2 * HCI) (%): C, 64.0; H, 7.8; N, 4.9. 61 WO 2005/082856 PCT/GB2005/000717 Example 24 2-Phenoxy-7-phenyl-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 N 0 *HCI 5 [0094] In analogy to the procedure described in Example 9, 2-chloro-7 pheny-7,8-dihydro-6H-quinolin-5-one was treated with phenol to give the title compound as a colorless solid. Physical characteristics are as follows: Mp 134-135 'C; 'H NMR (CDCl 3 , TMS) 5: 2.82 (dd, 17 and 12 Hz, IH); 2.97 10 (dd, 17 and 4 Hz, 1 H); 3.15 - 3.25 (m, 2H); 3.40 - 3.60 (m, 1 H); 6.78 (d, 8.5 Hz, 1 H); 7.13 - 7.48 (m, 1 OH) and 8.30 ppm (d, 8.5 Hz, I H). Example 25 2-Benzyloxy-7,7-pentamethylene-7,8-dihydro-6H-quinoline-5 -one 15 hydrochloride 0 *HCI [0095] To a solution of 7,7-pentamethylene-7,8-dihydro-1 H,6H-quinoline-2,5 dione (0.116 g, 0.5 mmol) in benzene (4 ml) was added silver carbonate 20 (0.055 g, 0.2 mmol) and benzyl bromide (0.09 ml, 0.78 mmol). The mixture was stirred and heated under reflux for 8 h, then it was diluted with benzene, filtered and evaporated to dryness. The residue was treated by dry HCI solution in diethyl ether to give the title compound (0.1 g, 55%) as a colorless solid. 25 Physical characteristics are as follows: Mp 276-277 *C; 'H NMR (CDCl 3 , TMS) 5: 1.47 (m, 10H); 2.61 (s, 2H); 3.46 (s, 2H); 5.66 (s, 2H); 6.98 (d, 9 Hz, IH); 7.3 - 7.5 (m, 5H); 7.90 (br s, 1H) 62 WO 2005/082856 PCT/GB2005/000717 and 8.45 ppm (d, 9 Hz, 1H); Anal. Found (C 21
H
23 N02 *HCI) (%): C, 69.8; H, 6.8; N, 3.8. Example 26 5 5-Oxo-2-(5-phenyl-thiophen-2-yl)-5,6,7,8-tetrahydro-quinoline-3 carbonitrile 0 - S [0096] To a solution of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3 10 carbonitrile (300 mg, 1.46 mmol) and 5-phenyl-thiophen-2-yl-boronic acid (446 mg, 2.19 mmol) in dioxane (3 ml) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) and 2M aqueous K2CO3 (0.7 ml). The mixture was stirred at reflux till complete (TLC; hexane-EtOAc, 2 : 1) consumption of 2-chloro-5-oxo-5,6,7,8-tetrahydro 15 quinoline-3-carbonitrile. Then water was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH 2
CI
2 - Hexane, 1 : 1), then heated under reflux in ethyl alcohol and filtered to give the title compound (220 mg, 46%) as a dark yellow solid. 20 Physical characteristics are as follows: Mp 221-224 0 C; 'H NMR (DMSO-D 6 , TMS) 5: 2.13 (m, 2H); 2.68 (t, 2H); 3.14 (t, 2H); 7.40 (t, IH); 7.47 (t, 2H); 7.70 (d, IH); 7.77 (d, 2H); 8.25 (d, IH); 8.54 (s, IH). 25 Example 27 2-Adamantan -1 -yI-7,7-pentamethylene-7,8-dihydro-6 H -quinol ine -5-one hydrochloride 63 WO 2005/082856 PCT/GB2005/000717 0 N *HCI [0097] In analogy to the procedure described in Example 13, 4-amino spiro[5.5]undec-3-en-2-one reacted with 1-adamantan-1-yl-propenone to 5 give the title compound as a colorless solid. Physical characteristics are as follows: Mp 221-222 *C; H NMR (CDCl 3 , TMS) 6:1.47 (br s,10H) 1.70-2.00 (m, 6H); 2.22 (br s, 3H); 2.36 (br s, 6H); 2.70 (s, 2H); 3.97 (s, 2H); 7.66 (d, 7.5 Hz, 1H) and 8.72 ppm (d, 7.5 Hz, 1H); Anal. Found (C 24
H
31 NO*HCI*2H 2 0) (%): 10 C, 68.3; H, 8.3; N, 3.1. Example 28 2-Ethoxy-7,7-pentamethylene-7,8-dihydro-6H-quinoline-5-one 0 N 0 CH 3 15 [0098] In analogy to the procedure described in Example 25, the title compound is obtained in significant yield. Example 29 2-(2-Hydroxyethoxy)-1-yl-7-7-pentamethylene-7,8-dihydro-6H-quinoline 20 5-one 0 OH [0099] In analogy to the procedure described in Example 9, the title compound is obtained in significant yield. 25 64 WO 2005/082856 PCT/GB2005/000717 Example 30 2-isopropyl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 H3C CH
H
3 C N
CH
3 [001001 In analogy to the procedure described in Example 13, the title 5 compound is obtained in significant yield. Example 31 2-Benzyloxy-7-ethyl-7,8-dihydro-6H-quinolin-5-one 0 H C 10 [001011 In analogy to the procedure described in Example 25, the title compound is obtained in significant yield. Example 32 7-(4-Dimethylamino-phenyl)-2-hexyl-7,8-dihydro-6H-quinolin-5-one 15 dihydrochloride 0 N N *2HCI1 [00102] In analogy to the procedure described in Example 13, 3 amino-5-(4-dimethylamino-phenyl)-cyclohex-2-en-1 -one reacted with non-1 20 en-3-one to give the title compound. Physical characteristics are as follows: 65 WO 2005/082856 PCT/GB2005/000717 Mp 195-196 C; 'H NMR (CDC 3 , TMS) 6: 0.87 (t, 6 Hz, 3H); 1.20 - 1.45 (m, 6H); 1.75 - 1.95 (m, 2H); 3.08 (m, 2H); 3.18 (s, 6H); 3.30 - 3.40 (m, 2H); 3.55 - 3.80 (m, 2H); 4.25 - 4.45 (m, 1 H); 7.49 (br s, 2H); 7.67 (d, 7 Hz, I H); 7.82 (br s, 2H); 8.77 (d, 7 Hz, I H); Anal. Found (C 23
H
30
N
2 O*2HCI*H 2 0) (%): 5 C, 62.0; H, 7.7; N, 5.8. Example 33 2-Cyclohexyl-7-propyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C N 10 [00103] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 34 2-(4-Methoxy-phenyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 N 15 0 [00104] In analogy to the procedure described in Example 13, 3 amino-6,6-dimethylcyclohex-2-en-1 -one reacted with 1-(4-methoxyphenyl) propenone to give the title compound. 20 Physical characteristics are as follows: Mp 158-159 *C; 'H NMR (CDCI 3 , TMS) 5: 1.24 (s, 6H); 2.05 (t, 6 Hz, 2H); 3.21 (t, 6 Hz, 2H); 3.87 (s, 3H); 7.00 (d, 8.8 Hz, 2H); 7.64 (d, 8 Hz, IH); 8.03 (d, 8.8 Hz, 2H) and 8.30 ppm (d, 8 Hz, 1H); Anal. Found (C 18
H
19
N
2 0) (%): C, 76.9; H, 6.7; N, 4.7. 25 66 WO 2005/082856 PCT/GB2005/000717 Example 35 cis,trans-6-Ethyl-2-(4-methoxy-phenyl)-cis,trans-6,8-dimethyl-7,8 dihydro-6H-quinolin-5-one 0
H
3 C N c
CH
3 5 [001051 In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 36 2-(3-Methoxy-phenyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 c O0
H
3 C N H 3 10 [00106] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 37 15 2-(3-Methoxy-phenyl)-6-ethyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C N CH3 [00107] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 20 Example 38 2-(3-Methoxy-phenyi)-6-methyl-7,8-dihydro-6H-quinolin-5-one 67 WO 2005/082856 PCT/GB2005/000717
H
3 C N O CH 3 [00108] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 39 2-Adamantan-1 -y-6-ethyl-8-methyl-7,8-dihydro-6H-quinolin-5-one hydrochloride dehydrate 0 N *HCI*2H20 10 [00109] In analogy to the procedure described in Example 13, 3 amino-6-ethyl-6-methylcyclohex- 2 -en-1 -one reacted with I-adamantan-1-yl propenone to give the title compound. Physical characteristics are as follows: Mp 131-132 'C; 'H NMR (CDCI 3 , TMS) &: 0.90 (t, 6.5 Hz, 3H); 1.21 (s, 3H); 15 1.55 - 2.10 (m, 1 OH); 2.22 (s, 3H); 2.36 (s, 6H); 3.80 - 4.15 (m, 2H); 7.66 (d, 8 Hz, 1H); 8.80 ppm (d, 8 Hz, 1H); Anal. Found (C 22
H
29 NO*HCI*2H20) (%):C, 67.0; H, 8.7; N, 3.3. Example 40 20 2-Ethoxy-7-furan-2-yl-7,8-dihydro-6H-quinolin-5-one 0 N 0 cH 3 68 WO 2005/082856 PCT/GB2005/000717 [00110] In analogy to the procedure described in Example 9, the title compound is obtained in significant yield. Example 41 5 2-Adamantan-1-yI-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 N *HCI [00111] In analogy to the procedure described in Example 13, 3 10 amino-6,6-dimethylcyclohex-2-en-1 -one reacted with 1-adamantan-1-yl propenone to give the title compound. Physical characteristics are as follows: Mp 203-204 "C. 1 H NMR (CDCI3, TMS) 5: 1.25 (s, 6H); 1.56 (m,1H); 1.70 2.00 (m, 6H); 2.10 (m, 1H); 2.24 (br s, 3H); 2.38 (br s, 6H); 3.85-4.15 (m, 15 2H); 7.66 (d, 6 Hz, 1H); 8.78 ppm (d, 6 Hz, 1H); Anal. Found (C21H 27 NO*2HCI) (%): C, 65.5; H, 7.5; N, 3.2. Example 42 20 (cis,trans) 2-Adamantan-1-yl-6-ethyl-8-methyl-7,8-dihydro-6H-quinolin 5-one and (cis,trans) 2-Adamantan-1-yl-8-ethyl-6-methyl-7,8-dihydro 6H-quinolin-5-one 0 0 N and [00112] In analogy to the procedure described in Example 13, the title 25 compound is obtained in significant yield. 69 WO 2005/082856 PCT/GB2005/000717 Example 43 cis,trans 6-Ethyl-2-hexyl-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C HC CH, 5 [00113] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 44 2-Cyclohexylmethyl-7,7-tetramethylene-7,8-dihydro-6H-quinolin-5-one 0 10 [00114] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 45 15 2-Hexyl-7-phenyl-7,8-dihydro-6H-quinolin-5-one 0 100115] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 20 Example 46 2-Cyclohexyl-7-isopropyl-7,8-dihydro-6H-quino[in-5-one 70 WO 2005/082856 PCT/GB2005/000717 0 Hac N CH, [001161 In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 47 2-Cyclohexyl-6-ethyl-6-methyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C N [00117] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 10 Example 48 2-(3-Methoxy-phnyl)-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one 0 HsC H3CN- 1 H N C' CH3 3 [00118] In analogy to the procedure described in Example 13, the title 15 compound is obtained in significant yield. Example 49 cis,trans 6-Ethyl-2-(3-methoxy-phenyl)-8-methyl-7,8-dihydro-6H quinolin-5-one and cis,trans 8-ethyl-2-(3-methoxy-phenyl)-6-methyl-7,8 20 dihydro-6H-quinolin-5-one 71 WO 2005/082856 PCT/GB2005/000717 O 0 N N and [00119] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 50 cis 2-(3-Methoxy-phenyl)-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 Hc N 3 CH 3 cH 3 7 [00120] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 10 Example 51 2-(3-Methoxy-phenyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 HC H3C N OCHa [00121] In analogy to the procedure described in Example 13, the title 15 compound is obtained in significant yield. Example 52 2-Hexyl-cis,trans-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one 72 WO 2005/082856 PCT/GB2005/000717 0
H
3 C N CH3
CH
3 [00122] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 53 2-Hexyl-7-propyl-7,8-dihydro-6H-quinolin-5-one 0 CH3 H 3 C N [00123] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 10 Example 54 6-Ethyl-2-hexyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C CH CH3 N [00124] In analogy to the procedure described in Example 13, the title 15 compound is obtained in significant yield. Example 55 2-Hexyl-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 N *HCI 20 73 WO 2005/082856 PCT/GB2005/000717 [00125] In analogy to the procedure described in Example 13, 3 amino-4,6,6-trimethylcyclohex-2-en-1 -one reacted with non-1-en-3-one to give the title compound. Physical characteristics are as follows: 5 Mp 199-200 C; 'H NMR (CDC 3 , TMS) 5: 0.86 (t, 6.5 Hz, 3H); 1.17 (s, 3H); 1.29 (s, 3H); 1.23 - 1.55 (m, 6H); 1.75 - 1.90 (m, 3H); 1.88 (d, 6.5 Hz, 3H); 2.21 (dd, 14.5 and 6 Hz, 1H); 3.30 - 3.70 (m, 2H); 3.83 - 3.97 (m, 1H); 7.61 (d, 8 Hz, IH) and 8.72 ppm (d, 8 Hz, IH); Anal. Found (C, 5
H
27 NO*HCI) (%): C, 69.6; H, 9.3; N, 4.4. 10 Example 56 2-Hexyl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 H3C I N3
H
3 [00126] In analogy to the procedure described in Example 13, the title 15 compound is obtained in significant yield. Example 57 cis,trans-8-Ethyl -2-hexyl-6-methyl-7,8-di hydro-6H-qui nolin-5-one and cis,trans-6-ethyl-2-hexyl-8-methyl-7,8-dihydro-6H-quinolin-5-one 20 0 0 and N N [00127] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 74 WO 2005/082856 PCT/GB2005/000717 Example 58 2-Hexyl-7-isopropyl-7,8-dihydro-6H-quinolin-5-one 0 H3C NCH3 CH3 [00128] In analogy to the procedure described in Example 13, the title 5 compound is obtained in significant yield. Example 59 2-(3-Methoxy-phenyl)-7,7-tetramethylene-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 N *HCI 10 [00129] In analogy to the procedure described in Example 13, 9 amino-spiro[4.5]dec-8-en-7-one was reacted with 1-(3 methoxyphenyl)propenone to give the title compound. 15 Physical characteristics are as follows: Mp 233-234 *C; 1 H NMR (CDCl 3 , TMS) 5: 1.45 - 1.95 (m, 8H); 2.77 (s, 2H); 4.04 (s, 5H); 7.20 (d, 8 Hz, I H); 7.40 - 7.65 (m, 2H); 7.85 - 8.05 (m, 2H) and 8.70 - 8.87 ppm (m, 1 H); Anal. Found (C 2 oH 2 1NO 2 *HCI) (%): C, 69.0; H, 6.4; N, 3.7. 20 75 WO 2005/082856 PCT/GB2005/000717 Example 60 2-(4-Methoxy-phenyl )-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 N 0 5 [00130] In analogy to the procedure described in Example 13, 3 amino-6-propylylcyclohex-2-en-1 -one was reacted with 1-(4 methoxyphenyl)propenone to give the title compound. Physical characteristics are as follows: 10 Mp 212-213 0 C; 1 H NMR (CDC1 3 , TMS) 5: 0.97 (t, 6.6 Hz,3H); 1.35 - 1.65 (m, 3H); 1.80 - 2.15 (m, 2H); 2.30 - 2.73 (m, 2H); 3.57 - 3.82 (m, 1 H); 3.90 (s, 3H); 4.29 (dt, 19 and 6 Hz, 1H); 7.12 (d, 8 Hz, 2H); 7.91 (d, 8 Hz, 1H); 8.28 (d, 8 Hz, 2H) and 8.74 ppm (d, 8 Hz, 1H); Anal. Found (CigH 2 1NO 2 *1.5HCl) (%): C, 64.9; H, 6.4; N, 3.7. 15 Example 61 2-(3-Methoxy-phenyl)-6-propyl-7,8-dihydro-6H-quinolin-5-one H3C N CH3 [00131] In analogy to the procedure described in Example 13, the title 20 compound is obtained in significant yield. Example 62 2-(4-Methoxy-phenyl)-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one 76 WO 2005/082856 PCT/GB2005/000717 0
H
3 C
H
3 C N
CH
3 -/CH 3 (00132} In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 63 2-(4-Methoxy-phenyl)-7,7-tetramethylene-7,8-dihydro-6H-quinolin-5-one 0
CH
3 [00133] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 10 Example 64 2-Hexyl-7-(3-methoxy-phenyl)-7,8-dihydro-6H-quinolin-5-one O1 CH3 H3C' N [00134] In analogy to the procedure described in Example 13, the title 15 compound is obtained in significant yield. Example 65 2-Hexyl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 77 WO 2005/082856 PCT/GB2005/000717 0 H3-- CH3
CH
3 [001351 In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 66 2-Benzyl-7,7-tetramethylene-7,8-dihydro-6H-quinolin-5-one hydrochloride 0 *HCI 10 [00136] In analogy to the procedure described in Example 13, 9 amino-spiro[4.5]dec-8-en-7-one was reacted with 1-phenylbut-3-en-2-one to give the title compound. Physical characteristics are as follows: Mp 202-203 DC; 1 H NMR (CDCI 3 , TMS) 5: 1.45 - 1.90 (m, 8H); 2.72 (s, 2H); 15 3.71 (s, 2H); 4.78 (s, 2H); 7.31 - 7.47 (m, 6H) and 8.62 ppm (d, 8 Hz, 1H). Example 67 2-Benzyl-6-propyl-7,8-dihydro-6H-quinolin-5-one 0 N 20 [00137] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 68 2-Benzyl-6-ethyl-7,8-dihydro-6H-quinolin-5-one 78 WO 2005/082856 PCT/GB2005/000717 H3C [00138] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 69 2-Benzyl-7-propyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C N [00139] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 10 Example 70 7-Ethyl-2-(4-methoxy-phenyl)-7,8-dihydro-6H-quinolin-S-one hydrochloride 0 N *HCI 0 15 [00140] In analogy to the procedure described in Example 13, 3 amino-5-ethylcyclohex-2-en-1 -one was reacted with 1-(4 methoxyphenyl)propenone to give the title compound. Physical characteristics are as follows: 20 Mp 232-233 oC; 1H NMR (CDCl3, TMS) 8: 1.06 (t, 7.4 Hz, 3H); 1.45-1.80 (m, 2H); 2.20-2.40 (m, 1H); 2.48 (dd, 16 and 12 Hz, IH); 2.93 (d, 16 Hz, IH); 3.32 (dd, 18 and 9 Hz, IH); 3.91 (s, 3H); 4.40-4.58 (d, 18 Hz, IH); 7.13 (d, 8.5 Hz, 2H); 7.90 (d, 8 Hz, 1H); 8.29 (d, 8.5 Hz, 2H) and 8.72 ppm (d, 8 Hz, 1H); Anal. Found (Cl8H19NO2*HCI) (%): C, 67.7; H, 6.3; N, 4.3. 25 79 WO 2005/082856 PCT/GB2005/000717 Example 71 2-(4-Methoxy-phenyl)-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 CH3 0CH3 [001411 In analogy to the procedure described in Example 13, the title 5 compound is obtained in significant yield. Example 72 2-(4-Methoxy-phenyl)-8-methyl-6-propyl-7,8-dihydro-6H-quinolin-5-one C3 N_ CH3 O'"CH 3 10 [00142] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 73 2-Benzyl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 cI 15 N [00143] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 74 20 2-Benzyl-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one 80 WO 2005/082856 PCT/GB2005/000717 0 H 3C
H
3 C N
CH
3 [00144] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 75 2-Benzyl-7-ethyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C N [00145] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 10 Example 76 (cis, trans) 2-Benzyl -6-ethyl-8-methyl-7,8-dihydro-6 H-quinolin-5-one and (cis, trans) 2-benzyl-8-ethyl-6-methyl-7,8-dihydro-6H-quinolin-5-one 0 0 N '~ and N_ 15 [00146] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 77 2-Cyclohexylmethyl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 H8c 20 H~C N 81 WO 2005/082856 PCT/GB2005/000717 [00147] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. Example 78 5 2-Cyclohexylmethyl-7-ethyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C N [00148] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 10 Example 79 2-Cyclohexylmethyl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C [00149] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 15 Example 80 2-Cyclohexylmethyl-6-ethyl-7,8-dihydro-6H-quinolin-5-one 0 HaC N [00150] In analogy to the procedure described in Example 13, the title 20 compound is obtained in significant yield. Example 81 2-(3-Methoxy-benzyl)-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one 82 WO 2005/082856 PCT/GB2005/000717 0 ' N [00151] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 5 Example 82 7-Isopropyl -2-pyrdin-3-yl-7,8-dihydro-6H-quinn -5-one hydrochloride 0 N *HCI 10 [00152 A mixture of 4 A molecular sieves (200 mg) and 1 -pyridin-3-yl prop-2-en-1-ol (270 mg, 2 mmol), 3-amino-5-isopropyl-cyclohex-2-enone (150 mg, 1 mmol), and 10% Pd/C (20 mg) in toluene (4 ml) was heated under reflux and blowing an air through a solution for 37 h. Mixture was filtered through a pad of celite and the filtrate was evaporated under reduced 15 pressure. The residue was purified by column chromatography on silica gel (dichloromethane - methanol mixtures) then it was treated by dry HCI solution in diethyl ether to give the title compound as a colorless solid. Physical characteristics are as follows: Mp 130-133 OC; 1 H NMR (CDCl 3 , TMS) 5: 1.04 and 1.05 (both d, 6.5 Hz, 6H); 20 1.76 (m, 6.5 Hz, 1H); 2.01 - 2.23 (m, 1H); 2.48 (dd, 16.5 and 13 Hz, IH); 2.88 (d, 16.5 Hz, IH); 2.99 (dd, 16.5 and 13 Hz, 1H); 3.33 (d, 16.5 Hz, IH); 7.88 (d, 6.5 Hz, IH); 8.06 (m, IH); 8.47 (d, 6.5 Hz, 1H); 8.82 (br. s, 1H); 9.09 (d, 6.5 Hz, 1H) and 9.60 ppm (br. s, 1H). 25 Example 83 2-Phenylethynyl-7,8-dihydro-6H-quinolin -5-one 83 WO 2005/082856 PCT/GB2005/000717 0 N [00153] To a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin 5-one (0.2 g, 1.1 mmol) and ethynylbenzene (0.17 g, 1.6 mmol) in triethylamine (7 ml) under an argon atmosphere was added tetrakis 5 (triphenylphosphine) palladium (0.02 g, 0.062 mmol). The mixture was heated at reflux for 3 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.04 g, 15%). Physical characteristics are as follows: 10 Mp 121-122 *C; 'H NMR (CDCl3, TMS) 8: 2.20 (m, 2H); 2.68 (t, 2H); 3.17 (t, 2H); 7.22-7.38 (m, 3H); 7.46 (d, 1H); 7.60 (d, 2H); 8.24 (d, 1H); MS 248 (M+1). Example 84 15 2-Biphenyl-4-yi-7,8-dihydro-6H-quinolin-5-one 0 [00154] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 20 Example 85 2-Hexylamino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile 84 WO 2005/082856 PCT/GB2005/000717 0 CN
N
N N H [00155] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 5 Example 86 2-(4-Methoxy-phenylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 AN H [00156] To a solution of 2-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin 5-one (0.35 g, 1.67 mmol) and 4-methoxyphenylamine (0.267 g, 2.2 mmol) 10 in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.22 g, 2.0 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.084 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.096 g, 19%) as a 15 colorless solid. Physical characteristics are as follows: Mp 149-150 *C; 'H NMR (CDCla, TMS) 5: 1.08 (s, 6H); 2.42 (s, 2H); 2.72 (s, 2H); 3.81 (s, 3H); 6.49 (d, 1H); 6.76 (br s, 1H); 6.91 (d, 2H); 7.24 (d, 2H); 8.01 (d, 1H); MS 297 (M+1). 20 Example 87 7,7-Dimethyl-5-oxo-2-[(tetrahydro-furan-2-ylmethyl)-amino]-5,6,7,8 tetrahydro-quinoline-3-carbonitrile 0 CN N N 25 [00157] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 85 WO 2005/082856 PCT/GB2005/000717 Example 88 2-Cyclopentylamino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile 0 5 H [00158] A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile (0.25 g, 1.06 mmol), cyclopentylamine (0.136 g, 1.6 mmol) and triethylamine (0.154 ml, 0.11 g, 1.1 mmol) in ethyl alcohol (3 ml) was heated at reflux for 3 h. Then water (10 ml) was added and the mixture 10 was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH 2
CI
2 - hexane, 1 : 1) to give the title compound (0.145 g, 48%). Physical characteristics are as follows: 15 Mp 154-156 "C; 'H NMR (DMSO-D 6 , TMS) 5: 1.00 (s, 6H); 1.50-65 (m, 4H); 1.65-75 (m, 2H); 1.9-2.0 (m, 2H); 2.40 (s, 2H); 2.80 (s, 2H); 4.48 (m, 1H); 7.55 (d, IH); 6.91 (d, 2H); 8.13 (d, 1H). Example 89 20 2-(2-Methoxy-ethylamino)-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile 0 CN N N H [00159] In analogy to the procedure described in Example 88, the title compound is obtained in significant yield. 25 Example 90 2-(Benzyl-methyl-amino)-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile 86 WO 2005/082856 PCT/GB2005/000717 0 N N [00160] In analogy to the procedure described in Example 88, the title compound is obtained in significant yield. 5 Example 91 5-Oxo-2-[(tetrahydro-furan-2-yl methyl)-amino]-5,6,7,8-tetrahydro quinoline-3-carbonitrile 0 N N 10 [00161] In analogy to the procedure described in Example 88, the title 10 compound is obtained in significant yield. Example 92 2-Cyclohexyiamino-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile N N H 15 [00162] A solution of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile (0.154 g, 0.75 mmol), cyclohexylamine (0.15 g, 1.5 mmol) and triethylamine (0.115 ml, 0.083 g, 0.82 mmol) in ethyl alcohol (3 ml) was heated at reflux for 3 h. Then water (10 ml) was added and the precipitated solid was filtered off and recrystallized from ethyl alcohol to give the title 20 compound (0.12 g, 59%). Physical characteristics are as follows: 87 WO 2005/082856 PCT/GB2005/000717 Mp 143-145 0 C; 'H NMR (DMSO-Ds, TMS) 5: 1.14 (t, IH); 1.31 (q, 2H); 1.43 (q, 2H); 1.61 (d 1H); 1.73 (d, 2H); 1.82 (d, 2H); 2.00 (m, 2H); 2.50 (m, 2H); 2.86 (t, 2H); 3.90 (t, 4H); 4.10 (m, I H); 7.34 (br s, 1 H); 8.14 (s, 1 H). 5 Example 93 5-Oxo-2-[(pyridin-2-ylmethyl)-amino]-5,6,7,8-tetrahydro-quinoline-3 carbonitrile 0 CN N N N H [00163] In analogy to the procedure described in Example 88, the title 10 compound is obtained in significant yield. Example 94 2-Azepan-1 -yl-5-oxo-5,6,7,8-tetrahydro-quinoline-3 -carbonitrile N 15 [00164] A solution of 2-chloro-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile (0.07 g, 0.34 mmol), azepane (0.07 g, 0.7 mmol) and triethylamine (0.052 ml, 0.07 g, 0.07 mmol) in ethyl alcohol (3 ml) was heated at reflux for 5 h. Then water (10 ml) was added and the precipitated solid was filtered off and recrystallized from ethyl alcohol to give the title 20 compound (0.035 g, 38%). Physical characteristics are as follows: Mp 76-78 0C; 'H NMR (DMSO-D6, TMS) : 1.52 (br s, 4H); 1.80 (br s, 4H); 2.02 (m, 2H); 2.50 (m, 2H); 2.86 (t, 2H); 3.90 (t, 4H); 8.16 (s, 1H). 25 Example 95 2-(Cyclohexyl-methyl-amino)-7,8-dihydro-6H-quinolin-5 -one 88 WO 2005/082856 PCT/GB2005/000717 0 N CH 3 N N [00165] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. 5 Example 96 2-Phenylamino-7/8-dihydro-6H-quinolin-5-one 0 CN H [00166] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 10 Example 97 2-(Cyclohexyl-methyl-amino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 0 H3CCH HN N 15 [00167] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. Example 98 2-(Benzyl-methyl-amino)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro 20 quinoline-3-carbonitrile 89 WO 2005/082856 PCT/GB2005/000717 N N [00168] A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile (0.22 g, 0.94 mmol), benzyl(methyl)amine (0.17 g, 1.4 mmol) and triethylamine (0.14 ml, 0.1 g, 1.0 mmol) in ethyl alcohol (3 ml) 5 was heated at reflux for 3 h. Then water (20 ml) was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH 2 Cl 2 - hexane, I : 1). The product obtained was recrystallized from ethyl alcohol to give the title compound (0.145 g, 48%). 10 Physical characteristics are as follows: Mp 97-99 *C; 'H NMR (DMSO-De, TMS) 5: 1.00 (s, 6H); 2.43 (s, 2H); 2.80 (s, 2H); 3.23 (s, 3H); 5.03 (s, 2H); 7.25-7.30 (m, 3H); 7.32-7.37 (m, 2H); 8.21 (s, IH). 15 Example 99 7,7-Dimethyl-5-oxo-2-[(pyridin-3 -ylmethyl)-amino]-5,6,7,8-tetrahydro quinoline-3-carbonitrile N N H [00169] In analogy to the procedure described in Example 98, the title 20 compound is obtained in significant yield. Example 100 7,7-Dimethyl-5-oxo-2-(4-phenyl-piperazin-1-yI)-5,6,7,8-tetrahydro quinoline-3-carbonitrile 90 WO 2005/082856 PCT/GB2005/000717 N, N N [00170] A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile (0.22 g, 0.94 mmol), 1-phenylpiperazine (0.23 g, 1.4 mmol) and triethylamine (0.14 ml, 0.1 g, 1.0 mmol) in ethyl alcohol (3 ml) 5 was heated at reflux for 4 h. Then water (20 ml) was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH 2
CI
2 - hexane, I : 2). The product obtained was recrystallized from ethyl alcohol to give the title compound (0.21 g, 62%). 10 Physical characteristics are as follows: Mp 167-170 *C; 'H NMR (DMSO-D 6 , TMS) 8: 1.00 (s, 6H); 2.45 (s, 2H); 2.84 (s, 2H); 3.33 (br s, 4H); 4.02 (br s, 4H); 6.80 (t, 1H); 6.97 (d, 2H); 7.23 (t, 2H); 8.25 (br s, I H). 15 Example 101 2-Azepan-1 -yl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0
H
3 C N
H
3 C [001711 In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. 20 Example 102 2-(4-Phenyl-piperazin-1 -yl)-7,8-dihydro-6H-quinoin-5-one 91 WO 2005/082856 PCT/GB2005/000717 0 N N N [00172] In analogy to the procedure described in Example 100, the title compound is obtained in significant yield. 5 Example 103 5-Oxo-2-phenylethynyl-5,6,7,8-tetrahydro-quinoline-3-carbonitrile 0 CN [00173] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 10 Example 104 7,7-Dimethyl-2-(1 -phenyl-ethylamino)-7,8-dihydro-6H-quinolin-5-one 0 N N [00174] In analogy to the procedure described in Example 98, the title 15 compound is obtained in significant yield. Example 105 2-(3,5-Dimethoxy-benzylamino)-7,8-dihydro-6H-quinolin-5-one 92 WO 2005/082856 PCT/GB2005/000717 0 N N N 'N 0 H [00175] in analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 5 Example 106 2-(3,5-Difluoro-benzylamino)-7,8-dihydro-6H-quinolin-5-one F N N ' H F [00176] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 10 Example 107 2-Biphenyl-4-yl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile 0 'N [00177] In analogy to the procedure described in Example 26, the title 15 compound is obtained in significant yield. Example 108 5-Oxo-2-(1 -phenyl -ethylamino)-5,6,7,8-tetrahydro-quinoline-3 20 carbonitrile 93 WO 2005/082856 PCT/GB2005/000717 N N H [00178] In analogy to the procedure described in Example 98, the title compound is obtained in significant yield. 5 Example 109 2-(3-Fluoro-benzylamino)-7,8-dihydro-6H-quinolin-5-one 0 - F N N H [00179] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 10 Example 110 3-[(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-yiamino)-methyl]-benzonitrile 0 - CN N N H 15 [00180] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. Example 111 2-Phenylamino-6,7,8,9,9a,10-hexahydro-5aH-benzo[g]quinolin-5 -one 0 NN 20 H 94 WO 2005/082856 PCT/GB2005/000717 [00181] To a solution of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H benzo[g]quinolin-5-one (0.4 g, 1.7 mmol) and aniline (0.204 g, 2.2 mmol) in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.223 g, 2.2 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.085 5 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.03 g, 6%) as a colorless solid. Physical characteristics are as follows: 10 Mp 214-216 0C; 'H NMR (DMSO-Ds, TMS) 6: 1.1-1.9 (m, 8H); 2.0-2.3 (m, 2H); 2.6-2.9 (m, 2,H); 6.73 (d, 1H); 6.98 (t, 1H); 7.30 (t, 2H); 7.74 (d, 2H); 7.86-7.94 (m, IH); 9.51 (br s, IH); MS 293 (M+1). Example 112 15 2-(1 -Phenyl-ethylamino)-6,7,8,9,9a,1 0-hexahydro-5aH-benzo[g]quinolin 5-one 0 N N H [00182] To a solution of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H benzo[g]quinolin-5-one (0.4 g, 1.7 mmol) and 1-phenyl-ethylamine (0.266 g, 20 2.2 mmol) in toluene (2 ml) under an argon atmosphere was added sodium tert-amylate (0.223 g, 2.03 mmol) and bis(tri-tert-butylphosphine)palladium (0.043 g, 0.084 mmol). The mixture was heated at reflux for 8 h. Then it was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel to give the title compound (0.13 g, 25 24%) as a colorless solid. Physical characteristics are as follows: Mp 156-158 0C; 1H NMR (DMSO-D 6 , TMS) 8: 1.0-1.1 (m, 1H); 1.2-1.3 (m, 2H); 1.44 (d, 3H); 1.65-1.85 (m, 4H); 2.00 (t, 2H); 2.20 (d, 1H); 2.50-2.72 (m, 2H); 5.18 (m, IH); 6.39 (d, IH); 7.19 (t, 1H); 7.29 (t, 2H); 7.36 (d, 2H) 7.70 30 (d, 1 H); 7.77 (br d, 1 H); MS 321 (M+1). 95 WO 2005/082856 PCT/GB2005/000717 Example 113 2-(Cyclohexyl-methyl-amino)-6,7,8,9,9a,10-hexahydro-5aH benzo[g]quinolin -5-one 0 N N 5 [00183] A mixture of 2-chloro-2,5a,6,7,8,9,9a, 1 0-octahydro-1 H benzo[g]quinolin-5-one (0.29 g, 1.23 mmol) and cyclohexyl(methyl)amine (1.39 g, 12.3 mmol) was stirred at 110 0 C for 9.5 h (TLC control; hexane EtOAc, 2 : 1). Then the mixture was separated by column chromatography on silica gel to give the title compound (0.2 g, 52%) as a colorless oil. 10 Physical characteristics are as follows: 1 H NMR (DMSO-D 6 , TMS) 5: 1.00-1.86 (m, 18H); 2.04 (dt, 2H); 2.21 (d, 1H); 2.60-2.75 (m, 2H); 2.93 (s, 3H); 4.43 (m, 1H); 6.57 (d, 1H); 7.82 (d, 1H); MS 313 (M+1). 15 Example 114 2-(4-Phenyl-piperazin-1-yl)-6,7,8,9,9a,10-hexahydro-5aH benzo[g]quinolin -5-one 0 N N N [00184] A mixture of 2-chloro-2,5a,6,7,8,9,9a, I 0-octahydro-1 H 20 benzo[g]quinolin-5-one (0.29 g, 0.123 mmol) and 1-phenylpiperazine (2.0 g, 12.3 mmol) was stirred at 100 'C for I h (TLC control; hexane-EtOAc, 2 : 1). Then the mixture was separated by column chromatography on silica gel to give the title compound (0.11 g, 25%) as a pale yellow solid. Physical characteristics are as follows: 25 Mp 164-166 *C; 'H NMR (DMSO-De, TMS) 6: 1.2-1.3 (m, 4H); 1.7-1.9 (m, 4H); 2.10 (m, 1H); 2.24 (m, 1H); 2.67-2.80 (m, 2H); 3.25 (m, 4H); 3.85 (m, 96 WO 2005/082856 PCT/GB2005/000717 4H); 6.77-6.83 (m, 2H); 6.98 (d, 2H); 7.24 (t, 2H); 7.88 ppm (d, 1 H); MS 362 (M+1). Example 115 5 2-Pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 NJ N N [00185] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 10 Example 116 2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one 0
CH
3 [00186] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 15 Example 117 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 97 WO 2005/082856 PCT/GB2005/000717 N OH [001871 In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 5 Example 118 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one compound is obtained in significant yield. 10 Example 119 2-(3-Fl uoro -ph enyl ethynyl)-7,8-d ihyd ro-6 H-qui noli n-5 -one 0 N F 98 WO 2005/082856 PCT/GB2005/000717 [00189] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. Example 120 5 2-(3-Chloro-phenyethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N [00190] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 10 Example 121 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 Br [00191] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 15 Example 122 3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile 99 WO 2005/082856 PCT/GB2005/000717 0 N CN [00192] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 5 Example 123 2-Thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 NN [001931 In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 10 Example 124 2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin- 5 -one 0 NO N [00194] In analogy to the procedure described in Example 83, the title 15 compound is obtained in significant yield. 100 WO 2005/082856 PCT/GB2005/000717 Example 125 2-(2-Phenyl-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 70 NN NN [00195] In analogy to the procedure described in Example 83, the title 5 compound is obtained in significant yield. Example 126 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one 0 N S N 10 [00196] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. Example 127 2-(3 -M ethoxy-4-pyri din -3-yl -phenyl)-7,8-di hyd ro-6 H-quinoli1n-5-o ne N 15 [00197] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 101 WO 2005/082856 PCT/GB2005/000717 Example 128 2-(3-Methoxy-4-pyridin-2-yl-phenyl)-7,8-dihydro-6H-quinolin-5-one 0
H
3 C [00198] In analogy to the procedure described in Example 26, the title 5 compound is obtained in significant yield. Example 129 2-Phenylethynyl-6,7,8,9, 9 a,10-hexahydro-SaH-benzo[g]quinolin- 5 -one 10 [00199] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. Example 130 3-(5-Oxo-5,5a,6,7,8,9,9a,10-octahydro-benzo[g]quinolin-2-yl) 15 benzonitrile 0 cN [00200] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 102 WO 2005/082856 PCT/GB2005/000717 Example 131 2-Pyridin-3-yI-6,7,8,9,9a,10-hexahydro-5aH-benzo[g]quinolin-5-one 0 CN N [00201] In analogy to the procedure described in Example 26, the title 5 compound is obtained in significant yield. Example 132 2-Piperidin-1-yl-6,7,8,9,9a,10-hexahydro-SaH-benzo[g]quinolin-5-one 0 N 10 [00202] In analogy to the procedure described in Example 114, the title compound is obtained in significant yield. Example 133 4-Chloro-5-oxo-2-(4-phenyl-pi perazin-1-yl)-5,6,7,8-tetrahydro-quinoline 15 3-carbonitrile ci 0 N N N [00203] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 20 103 WO 2005/082856 PCT/GB2005/000717 Example 134 4-Bromo-5-oxo-2-(4-phenyi-piperazin-1 -yI)-5,6,7,8-tetrahydro-quinoline 3-carbonitrile Br 0 N N N 5 [00204] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 135 4-Methoxy-5-oxo-2-(4-phenyl-piperazin-1 -yl)-5,6,7,8-tetrahydro 10 quinoline-3-carbonitrile CH N N N [00205] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 15 Example 136 4-Ethoxy-5-oxo-2-(4-phenyl-piperazin-1 -yl)-5,6,7,8-tetrahydro-quinoline 3-carbonitrile 104 WO 2005/082856 PCT/GB2005/000717
CH
3 o 0 N N N N [00206] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 5 Example 137 4' 4-Ethoxy-7,7-dimethyl-5-oxo-2-(4-phenyl-piperazin-1 -yl)-5,6,7,8 tetrahydro-quinoline-3-carbonitrile
CH
3 o 0 N>
CH
3 N
CH
3 NJ [00207] In analogy to the procedure described in Example 7 or 12, the 10 title compound is obtained in significant yield. Example 138 4-Methoxy-7,7-dimethyl-6-oxo-2-(4-phenyl-piperazin-1 -yl)-5,6,7,8 tetrahydro-quinoline-3-carbonitrile o'0 N CH 3 N N OH 3 NJ 15 105 WO 2005/082856 PCT/GB2005/000717 [00208] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 139 5 4-Chloro-7,7-dimethyl-5-oxo-2-(4-phenyl-piperazin-I -yI)-5,6,7,8 tetrahydro-quinoline-3-carbonitrile N>
CH
3 N N CH 3 NJ [002091 In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 10 Example 140 4-Bromo-7,7-dimethyl-5-oxo-2-(4-phenyl-piperazin-I -yl)-5,6,7,8 tetrahydro-quinoline-3-carbonitrile Br 0 N CH, N N CH 3 N 15 [002101 In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 106 WO 2005/082856 PCT/GB2005/000717 Example 141 4-Bromo-7,7-dimethyl-5-oxo-2-(4-phenyI-piperidin-1 -yl)-5,6,7,8 tetrahydro-quinoline-3-carbonitrile Br 0
CH
3 N N CH 3 5 [002111 In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 142 4-Chloro-7,7-dimethyl-5-oxo-2-(4-phenyI-piperidin-1-yl)-5,6,7,8 10 tetrahydro-quinoline-3-carbonitrile CI 0
CH
3 N N CH 3 [00212] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 107 WO 2005/082856 PCT/GB2005/000717 Example 143 4-Methoxy-7,7-dimethyl-5-oxo-2-(4-phenyi-piperidin-1 -yl)-5,6,7,8 tetrahydro-quinoline-3-carbonitrile
H
3 C O a CH, N NH 5 [00213] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 144 4-Ethoxy-7,7-dimethyl-5-oxo-2-(4-phenyl-piperidin-I -yl)-5,6,7,8 10 tetrahydro-quinoline-3-carbonitrile
CH
3 0 0 N> CH 3 N CH 3 [00214] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 15 Example 145 4-(2-Hydroxy-ethoxy)-7,7-dimethyl-5-oxo-2-( 4 -phenyI-piperidin-1 -yl) 5,6,7,8-tetrahydro-quinoline-3-carbonitrile 108 WO 2005/082856 PCT/GB2005/000717 HO 0 0
CH
3 N N CH 3 [00215] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 5 Example 146 3-Chloro-7,7-dimethyl-2-(4-phenyl-piperidin-I -yl)-7,8-dihydro-6H quinolin-5-one 0 ICI C
CH
3 N N CH 3 [00216] In analogy to the procedure described in Example 7 or 12, the 10 title compound is obtained in significant yield. Example 147 3-Bromo-7,7-dimethyl-2-(4-phenyl-piperidin-1 -yl)-7,8-dihydro-6H quinolin-5-one 0 Br B r C H s N N CH3 15 109 WO 2005/082856 PCT/GB2005/000717 [00217] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 148 5 3-Fluoro-7,7-dimethyl-2-(4-phenyl-piperidin-1 -yI)-7,8-dihydro-6H quinolin-5-one 0 F cH 3 N N CH 3 [00218] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 10 Example 149 3-Methoxy-7,7-dimethyl-2-(4-pheny-piperidin-1 -yI)-7,8-dihydro-6H quinolin-5-one cH 3 o
CH
3 N N CH 3 15 [00219] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 150 7,7-Dimethyl-3-nitro-2-(4-phenyl-piperidin-1-yI)-7,8-dihydro-6H-quinolin 20 5-one 110 WO 2005/082856 PCT/GB2005/000717 0 0
CH
3 N N CH, [002201 In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 5 Example 151 7,7-Dimethyl-3-nitro-2-(4-phenyI-piperazin-1 -yl)-7,8-dihydro-6H quinolin-5-one 0 0 oo CH, N N CH 3 N 7 [00221] In analogy to the procedure described in Example 7 or 12, the 10 title compound is obtained in significant yield. Example 152 3-Fluoro-7,7-dimethyl-2-(4-pheny-piperazin-1 -yI)-7,8-dihydro-6H quinolin-5-one 0 F CH3 N N" cH 3 N 15 [00222] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 153 111 WO 2005/082856 PCT/GB2005/000717 3-Bromo-7,7-dimethyl-2-(4-phenyl-piperazin-1 -yl)-7,8-di hydro-6H quinolin-5-one 0 Br
CH
3 N CH 3 N 5 [00223] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 154 3-Chloro-7,7-dimethyl-2-(4-phenyl-piperazin-1 -yl)-7,8-dihydro-6H 10 quinolin-5-one 0 CHS N N
CH
3 N [00224] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 15 Example 155 3-Methoxy-7,7-dimethyl-2-(4-phenyl-piperazin-1 -yl)-7,8-dihydro-6H quinolin-5-one
CH
3 0 CH N N CH 3 N 112 WO 2005/082856 PCT/GB2005/000717 [00225] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 156 5 2-[4-(4-Methoxy-phenyl)-piperazin-1 -yl]-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile 0 NC , CH 3 NN CH 3 N
H
3 Cso [00226] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 10 Example 157 2-[4-(4-Fluoro-phenyl)-piperazin-1 -yl]-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile 0 NC
CH
3 N N
CH
3 N F 15 [00227] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 158 2-(5-m-Tolyl-thiazol-2-yl)-7,8-dihydro-6H-quinolin-5-one 0 1N- S N ~ \ 20 113 WO 2005/082856 PCT/GB2005/000717 [00228] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 159 5 2-[5-(3-Hydroxy-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5-one 0 6 N S OH [00229] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 10 Example 160 2-[5-(3-Methoxy-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5-one 0 N S 00 0 [00230] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 15 Example 161 2-[5-(3-Fluoro-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5-one 0 N jS~ F [00231] In analogy to the procedure described in Example 26, the title 20 compound is obtained in significant yield. Example 162 2-[5-(3-Chloro-ph enyl)-thiazol-2-y]-7,8-dihydro-6H-quinolin-5-one 114 WO 2005/082856 PCT/GB2005/000717 0 N S C1 [00232] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 5 Example 163 2-[5-(3-Bromo-phenyl)-thi azol -2-yl]-7,8-dihydro-6H-quinolin -5 -one 0 N N Br [00233] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 10 Example 164 3 -[2-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-yI)-thiazol-5-yl]-benzonitrile 0 N I CN [00234] In analogy to the procedure described in Example 26, the title 15 compound is obtained in significant yield. Example 165 2 -[5-(3,5-Dimethoxy-phenyl)-thiazol-2-yl]- 7
,
8 -dihydro-6H-quinolin-5-one 0 0 NNIC 0 115 WO 2005/082856 PCT/GB2005/000717 [00235] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 166 5 2-[2-(3,5-Di methoxy-phenyl)-vinyl]-.7,8-dihydro-6H-quin olin -5 -one 0 o [00236] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 10 Example 167 2-[5-(3-Fluoro-5-methyl-phenyl)-thiazol-2-yI]-7,8-dihydro-6H-quinolin-5 one 0 N S F [00237] In analogy to the procedure described in Example 26, the title 15 compound is obtained in significant yield. Example 168 3-Fluoro-5-[2-(5-oxo-5,6,7,8 -tetrahydro-quinolin-2 -yl)-th iazol -5-yl] benzonitrile 0 CN & N IS C 20 F [00238] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 116 WO 2005/082856 PCT/GB2005/000717 Example 169 2-[5-(3-Fl uoro-5 -methoxy-phenyl)-thiazol-2 -yl]-7,8-dihydro-6H-quinolin 5-one 0 N 5 F [00239] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 170 10 2-[5-(3-Fluoro-5-pyridin-2-yl-phenyl)-thiazol-2-yI]-7,8-dihydro-6H quinolin-5-one o - S -N N J F [00240] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 15 117 WO 2005/082856 PCT/GB2005/000717 Example 171 2-[5-(3-Fluoro-5-pyridin-3-yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H quinolin-5-one & NN - S N F 5 [00241] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 172 2-Adamantan-1 -yl-6,7,8,9,9a, 0-hexahydro-5aH-benzo[g]quinolin-5-one 10 N [00242] In analogy to the procedure described in Example 13, the title compound is obtained in significant yield. 15 Example 173 7,7-Dimethyl-2-pyridin-3-ylethynyl-7,8-dihydro-6H-quinolin-5-one 0 [00243] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 20 Example 174 7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one 118 WO 2005/082856 PCT/GB2005/000717 N [00244] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 5 Example 175 2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one N OH [00245] In analogy to the procedure described in Example 83, the title 10 compound is obtained in significant yield. Example 176 2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one /6N 15 [00246] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 119 WO 2005/082856 PCT/GB2005/000717 Example 177 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 [002471 In analogy to the procedure described in Example 83, the title 5 compound is obtained in significant yield. Example 178 2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinol in -5-one N CI 10 [00248] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. Example 179 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 15 Br [00249] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 120 WO 2005/082856 PCT/GB2005/000717 Example 180 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl) benzonitrile N CN 5 [00250] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. Example 181 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8 -dihydro-6H-quinolin-5-one 100 S 10 N [00251] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. Example 182 15 7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quin olin-5 -one I'NO N [00252] In analogy to the procedure described in Example 83, the title compound is obtained in significant yield. 20 121 WO 2005/082856 PCT/GB2005/000717 Example 183 2-(3-Methoxy-4-pyridin-3-yl-phenyl)-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 0 N /O1 N 5 [00253] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 184 2-(3-Methoxy-4-pyridin-2-yl-phenyl)-7,7-dimethyl-7,8-dihydro-6H 10 quinolin-5-one 0 N O N/ [002541 In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 15 Example 185 2-[5-(3-Fluoro-5-pyridin-4-yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H quinolin-5-one N 0 / N F [00255] In analogy to the procedure described in Example 26, the title 20 compound is obtained in significant yield. 122 WO 2005/082856 PCT/GB2005/000717 Example 186 2-[5-(3-Fluoro-5-morpholin-4-yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H quinolin-5-one 0 0 N 'N S I F 5 [00256] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 187 2-[5-(3-Fluoro-5-piperidin-1 -yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H 10 quinolin-5-one 0 N N N r S F [00257] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 15 Example 188 7,7-Dimethyl-2-(5-m-tolyl-thiazol-2 -y)-7,8-dihydro-6-quinolin-5-one 0 N I N [00258] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 20 123 WO 2005/082856 PCT/GB2005/000717 Example 189 2-[5-(3-Hydroxy-phenyl)-thiazol-2-yl-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 0 OH 5 [00259] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 190 2-[5-(3-Methoxy-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8-dihydro-6H 10 quinolin-5-one 0 N
S
N 0 [00260] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 15 Example 191 2-[5-(3-Fluoro-phenyl)-thiazol-2-yI]-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 0 F [00261] In analogy to the procedure described in Example 26, the title 20 compound is obtained in significant yield. 124 WO 2005/082856 PCT/GB2005/000717 Example 192 2-[5-(3-Chloro-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 0 N C1 5 [00262] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 193 2-[5-(3-Bromo-phenyl)-thiazol-2-yI]-7,7-dimethyl-7,8-dihydro-6H 10 quinolin-5-one 0 N S N / Br [00263] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 15 Example 194 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-thiazol-5-yl] benzonitrile 0 N C N [00264] In analogy to the procedure described in Example 26, the title 20 compound is obtained in significant yield. Example 195 2-[5-(3,5-Dimethoxy-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 125 WO 2005/082856 PCT/GB2005/000717 0 0 N S 0 [00265] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 5 Example 196 2-[2-(3,5-Dimethoxy-phenyl)-vinyl]-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 0 N 01-1 [00266] In analogy to the procedure described in Example 13, the title 10 compound is obtained in significant yield. Example 197 2-[5-(3-Fluoro-5-methyl-phenyl)-thiazol-2-yI]-7,7-dimethyl-7,8-dihydro 6H-quinolin-5-one 0 N 15 F [00267] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 126 WO 2005/082856 PCT/GB2005/000717 Example 198 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-thiazol-5-yI]-5 fluoro-benzonitrile 0 CN N -) F 5 [002681 In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 199 2-[5-(3-Fluoro-phenyl)-thiazol-2-y]-7,8-dihydro-6H-quinolin-5 -one 0 N- I N 10 F [00269] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 200 15 2-[5-(3-Fluoro-5-methoxy-phenyl)-thiazol-2-yI]-7,7-dimethyl-7,8-dihydro 6H-quinolin-5-one 0 S N F [00270] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 20 Example 201 2-[5-(3-Fluoro-5-pyridin-2-yI-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8 dihydro-6H-quinolin-5-one 127 WO 2005/082856 PCT/GB2005/000717 o/\ NN F [00271] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 5 Example 202 2-[5-(3-Fluoro-5-pyridin-3-yl-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8 dihydro-6H -quinolin-5-one o N N NJ F [00272] In analogy to the procedure described in Example 26, the title 10 compound is obtained in significant yield. Example 203 2-[5-(3-Fluoro-5-pyridin-4-yI-phenyl)-thiazol-2-yI]-7,7-dimethyl-7,8 dihydro-6H-quinolin-5-one N N 15 F [00273] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 204 20 2-[5-(3-Fluoro-5-morpholin-4-yI-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8 dihydro-6H-quinolin-5-one 128 WO 2005/082856 PCT/GB2005/000717 0 0 N N N S / F [00274 In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 5 Example 205 2-[5-(3-Fl uoro-5-piperi din-1 -yI-phenyl)-thiazol-2-yl]-7,7-dimethyl-7,8 dihydro-6H -quinolin-5-one 0 N N N F [00275] In analogy to the procedure described in Example 26, the title 10 compound is obtained in significant yield. Example 206 2-(5-m-Tolyl-oa,3,4]oxadiazo-2 -y)-7,8-dihydro-6H-quinoin-5 -one 0 1 6- 0 N N) 15 [00276] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 207 0 N N 20 129 WO 2005/082856 PCT/GB2005/000717 [00277] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 208 5 2-(1 -m-Tolyl-1 H-imidazol-4-y)-7,8-dihydro-6H-quinolin-5-one 0 'N- ~N N [00278] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 10 Example 209 2-(5-m-Tolyl-isoxazol-3-y)-7,8-dihydro-6H-quinolin-5 -one 0 N N'O0 [00279] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 15 Example 210 2-[5-(3-Fluoro-phenyl)-oxazol-2-yl]-7,8-dihydro-6H-quinolin-5-one 0 N / F [00280] In analogy to the procedure described in Example 26, the title 20 compound is obtained in significant yield. Example 211 2-[1-(3-Fluoro-phenyl)-1 H-imidazol-4-y]-7,8-dihydro-6H-quinolin-5-one 130 WO 2005/082856 PCT/GB2005/000717 0 'N N N -/ F [00281] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 5 Example 212 2-[5-(3-Fluoro-phenyl)-isoxazol-3-yl]-7,8-dihydro-6H-quinolin-5-one 0 'N
N-
0 F [00282] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 10 Example 213 3-[2-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-oxazol-5-yl]-benzonitrile 0 N /) CN [00283] In analogy to the procedure described in Example 26, the title 15 compound is obtained in significant yield. Example 214 3-[1-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-1H-imidazol-4-yI] benzonitrile 0 &N N N\ 20 CN 131 WO 2005/082856 PCT/GB2005/000717 [002841 In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 215 5 3-[3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-isoxazol-5-yl]-benzonitrile 0 N \~~ N-0 CN [00285] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 10 Example 216 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin- 2 -yi)-oxazol-5-y] benzonitrile 0 N 0 CN [00286] In analogy to the procedure described in Example 26, the title 15 compound is obtained in significant yield. Example 217 3-[1-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-1 H-imidazol-4 yl]-benzonitrile 0 N N 20 CN [00287] In analogy to the procedure described in Example 86 the title compound is obtained in significant yield. 132 WO 2005/082856 PCT/GB2005/000717 Example 218 3-[3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-isoxazol-5-y] benzonitrile 0 N \ N'O CN 5 [00288] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 219 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-oxazol-5-yl]-5 10 fluoro-benzonitrile 0 CN N -) F [00289] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 15 Example 220 3-[1-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-y)-1 H-imidazol-4 yl]-5-fluoro-benzonitrile 0 CN N N N F F [00290] In analogy to the procedure described in Example 86 the title 20 compound is obtained in significant yield. Example 221 3-[3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-isoxazo-5-yi] 5-fluoro-benzonitrile 133 WO 2005/082856 PCT/GB2005/000717 0 CN N \
N-
0 F [00291] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. 5 Example 222 7,7-Dimethyl-2-(5-pyridin-3-yl-thiazol-2-yl)-7,8-dihydro-6H-quinolin-5 one 0 N [00292] In analogy to the procedure described in Example 26, the title 10 compound is obtained in significant yield. Example 223 2-(5-Pyridin-3-yl-thiazol-2-yl)-7,8-dihydro-6H-quinolin-5 -one 0 N S N 15 [00293] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 224 2-(3-Methoxy-4-pyridin-2-yl-phenylamino)-7,7-dimethyl-7,8-dihydro-6H 20 quinolin-5-one 134 WO 2005/082856 PCT/GB2005/000717 0 N NH 0 [00294] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 5 Example 225 2-(3-Methoxy-4-pyridin-3-yl-phenylamino)-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 0 N N. 0 [00295] In analogy to the procedure described in Example 86, the title 10 compound is obtained in significant yield. Example 226 2-(3-Fluoro-4-pyridin-2-yl-phenylamino)-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one 0 N NH F N 15 135 WO 2005/082856 PCT/GB2005/000717 [00296] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. Example 227 5 7,7-Dimethyl-2-(pyridin-2-ylamino)-7,8-dihydro-6H-quinolin-5-one 0 N NH N -) [00297] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 10 Example 228 2-(3-M ethoxy-phenylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 N NH [00298] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 15 Example 229 2-(Indan-2-ylamino)-7,7-dimethyl-5-oxo-5,6,7,8tetrahydro-quinoline-3 carbonitrile 0 N NH 136 WO 2005/082856 PCT/GB2005/000717 [00299] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 230 5 7,7-Dimethyl-5-oxo-2-phenylamino-5,6,7,8-tetrahydro-quinoline-3 carbonitrile 0 cN N NH [003001 In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 10 Example 231 2-(4-Methoxy-phenylamino)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile 0 CN 15 [00301] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 137 WO 2005/082856 PCT/GB2005/000717 Example 232 2-(4-Methoxy-phenylamino)-7,7-dimethyl-3-nitro-7,8-dihydro-6H quinolin-5-one 0
NO
2 N- NH 1 0 5 [00302] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. Example 233 2-(1,3-Dihydro-isoindol-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro 10 quinoline-3-carbonitrile 0 CN N N [00303] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 15 Example 234 2-(3,4-Dihydro-1 H-isoquinolin-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile 0 CN N N [00304] In analogy to the procedure described in Example 7 or 12, the 20 title compound is obtained in significant yield. 138 WO 2005/082856 PCT/GB2005/000717 Example 235 2-(Adamantan-1 -ylamino)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3 -carbonitrile 0 CN N_ NH 5 [00305] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. Example 236 7,7-Dimethyl-3-morpholin-4-yI-2-(4-phenyl-piperidin-1 -yl)-7,8-dihydro 10 6H-quinolin-5-one 0 o N,, N N% [00306] In analogy to the procedure described in Example 7 or 12, the title compound is obtained in significant yield. 15 Example 237 2-(3-Fl uoro-4-pyridin -3-yl -phenylamino)-7,7 -dimethyl -7,8-dihydro-6H quinolin-5-one 0 N NH F NN. 139 WO 2005/082856 PCT/GB2005/000717 [00307] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. Example 238 5 2-(3-Methoxy-4-pyridin-2-yl-phenylamino)-7,8-dihydro-6H-quinolin-5 one 0 N NH aN [00308] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 10 Example 239 2-(3-Methoxy-4-pyridin-3-yi-phenylamino)-7,8-dihydro-6H-quinolin-5 one 0 NNH NN. 15 [00309] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. Example 240 2-(3-Fluoro-4-pyridin-2-yl-phenylamino)-7,8-dihydro-6H-quinolin-5-one 140 WO 2005/082856 PCT/GB2005/000717 0 N NH F N [00310] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 5 Example 241 2-(3-Fluoro-4-pyridin-3-yl-phenylamino)-7,8-dihydro-6H-quinolin-5-one 0 N NH F N-. [00311] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 10 Example 242 7,7-Dimethyl-2-(pyrdin-3-ylamino)-7,8-dihydro-6H-quinolin-5-one 0 N [00312] In analogy to the procedure described in Example 86, the title 15 compound is obtained in significant yield. 141 WO 2005/082856 PCT/GB2005/000717 Example 243 7,7-Dimethyl-2-(pyridin-4-ylamino)-7,8-dihydro-6H-quinolin-5-one 0 fN- N H NH [00313] In analogy to the procedure described in Example 86, the title 5 compound is obtained in significant yield. Example 244 5-Oxo-2-(5-phenyl-thiazol-2-yl)-5,6,7,8-tetrahydro-quinoline-3 carbonitrile 0 CN - S 6N-I 10 N [00314] In analogy to the procedure described in Example 26, the title compound is obtained in significant yield. Example 245 15 2-(3-Methoxy-4-pyridin-2-yl-phenylamino)-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile 0 NN 0 [00315] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 20 142 WO 2005/082856 PCT/GB2005/000717 Example 246 2-(3-Methoxy-4-pyridin-3-yl-phenylamino)-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile 0 CN N NH N, 5 [00316] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. Example 247 7,7-Dimethyl-5-oxo-2-(pyridin- 4 -yl amino)-5,6,7,8-tetrahydro-quinol ine-3 10 carbonitrile 0 NCN N' NH (N1 [00317] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 15 Example 248 7,7-Dimethyl-3-nitro-2-(pyridin- 4 -ylamino)-7,8-dihydro-6H-quinolin-5 one 0 O O N NH CN 143 WO 2005/082856 PCT/GB2005/000717 [00318] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. Example 249 5 2-(3,5-Dimethoxy-phenylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 0 N NH NH 0 0 [00319] In analogy to the procedure described in Example 86, the title compound is obtained in significant yield. 10 Example 250 2-Benzylsulfanyl-7,7-dimethyl-3-nitro-7,8-dihydro-6H-quinolin-5-one 0 N 02 N S [00320] The title compound is obtained in significant yield according to 15 the procedures shown in Scheme 1. Example 251 2-Benzylsulfanyl-3-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one 0 CI N S 20 [00321] The title compound is obtained in significant yield according to the procedures shown in Scheme 1. 144 WO 2005/082856 PCT/GB2005/000717 Example 252 7,7-Dimethyl-3-nitro-2-piperidin-1 -yl-7,8-dihydro-6H-quinolin-5-one 0
NO
2 [00322] In analogy to the procedure described in Example 94 the title 5 compound is obtained in significant yield. Example 253 3-Chloro-7,7-dimethyl-2-piperidin-1 -yl-7,8-dihydro-6H-quinolin-5-one 0 / N 1 NC 10 [00323] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. Example 254 2-Cyclopentylamino-7,7-dimethyl-3-nitro-7,8-dihydro-6H-quinolin-5-one 0 N NH 15 (00324] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. Example 255 20 3-Chloro-2-cyclopentylamino-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 145 WO 2005/082856 PCT/GB2005/000717 0 CI NNH 6 [00325] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. 5 Example 256 3-Chloro-2-[4-(4-methoxy-phenyl)-piperazin-1-yI]-7,7-dimethyl-7,8 dihydro-6H -quinolin-5-one 0 C N N LN [00326] In analogy to the procedure described in Example 94, the title 10 compound is obtained in significant yield. Example 257 2-[4-(4-Methoxy-phenyl)-piperazin-1-yI]-7,7-dimethyl-3-nitro-7,8 dihydro-6H-quinolin-5-one 0
NO
2 N N N 15 [00327] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. 146 WO 2005/082856 PCT/GB2005/000717 Example 258 7,7-Dimethyl-5-oxo-2-(3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1 -yl) 5,6,7,8-tetrahydro-quinoline-3-carbonitrile 0 ON N N, 5 [00328] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. Example 259 2-[4-(4-Methoxy-phenyl) -piperidi n-1 -yI] -7,7-dimethyl -5-oxo-5,6,7, 8 10 tetrahydro-quinoline-3-carbonitrile 0 CN N N 0 [00329] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. 15 Example 260 2-[l-(4-Methoxy-phenyl)-piperidin-4-yl]-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile 0 CN N_ N [00330] In analogy to the procedure described in Example 13, the title 20 compound is obtained in significant yield. 147 WO 2005/082856 PCT/GB2005/000717 Example 261 7,7-Dimethyl-5-oxo-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7 ylamino)-5,6,7,8-tetrahydro-quinoline-3-carbonitrile 0 CN N NH 5 [00331] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. Example 262 0 N NH 10 [00332] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. Example 263 15 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-3-nitro-7,8-dihydro-6H quinolin-5-one 0 4NH 148 WO 2005/082856 PCT/GB2005/000717 [00333] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. Example 264 5 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one 0 N NH [00334] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. 10 Example 265 2-(4-M ethoxy-cyclohexylamin o) -7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3 -carbon itrile 0 N N_ N H 15 [00335] In analogy to the procedure described in Example 94, the title compound is obtained in significant yield. [00336] Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art 20 known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their 149 WO 2005/082856 PCT/GB2005/000717 diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, 5 provided that the reaction occurs stereoselectively. Stereoisomeric forms of Formula IA are obviously intended to be included within the scope of this invention. ADDITION SALTS 10 [00337] For therapeutic use, salts of the compounds of Formula IA are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not 15 are included within the ambit of the present invention. The pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms which the compounds of Formula IA are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g. hydrohalic 20 acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3 propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4 25 methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2 hydroxybenzoic and the like acids. Conversely, the salt form can be converted by treatment with alkali into the free base form. PHARMACEUTICAL COMPOSITIONS 30 [00338] The active ingredients of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or 150 WO 2005/082856 PCT/GB2005/000717 capsules filled with the same, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise 5 conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one (1) to one hundred (100) milligrams of active 10 ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms. [00339] The term "carrier" applied to pharmaceutical compositions of 15 the invention refers to a diluent, excipient, or vehicle with which an active compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, 20 sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 18 th Edition. METHOD OF TREATING [00340] Due to their high degree of activity and their low toxicity, 25 together presenting a most favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth 30 elsewhere in this application, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an 151 WO 2005/082856 PCT/GB2005/000717 effective amount. Suitable dosage ranges are 1-1000 milligrams daily, preferably 10-500 milligrams daily, and especially 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the 5 subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge. [00341] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is 10 sufficient to result in a desired activity upon administration to a living animal body in need thereof. [00342] The active agents of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by 15 inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route. The active agents may be administered orally in the form of a capsule, a tablet, or the like (see Remington's Pharmaceutical Sciences, Mack 5 Publishing Co., Easton, PA). The orally administered medicaments 20 may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution controlled matrices, and erodible/degradable matrices. [00343] For oral administration in the form of a tablet or capsule, the 25 active drug component can be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium 30 hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth 152 WO 2005/082856 PCT/GB2005/000717 or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the drug components can be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., 5 sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium 10 ascorbate, citric acid) can also be added to stabilize the dosage forms. [00344] The tablets can be coated by methods well known in the art. The compositions of the invention can be also introduced in microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA). 15 Liquid preparations for oral administration can take the form of, for example, solutions, syrups, emulsions or suspensions, or they can be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration can be suitably formulated to give controlled or postponed release of the active compound. 20 [00345] The active drugs can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or 25 phosphatidylcholines, as is well known. [00346] Drugs of the invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drugs may also be coupled with soluble 30 polymers as targetable drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, active drug may be coupled to a class of biodegradable polymers useful in achieving controlled 153 WO 2005/082856 PCT/GB2005/000717 release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of 5 hydrogels. [00347] For administration by inhalation, the therapeutics according to the present invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a 10 suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix 15 of the compound and a suitable powder base such as lactose or starch. [00348] The formulations of the invention can be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal 20 (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can 25 contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. 30 [00349] Compositions of the present invention can also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides). 154 WO 2005/082856 PCT/GB2005/000717 [00350] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration. The pack may, for example, comprise metal or 5 plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an.appropriate container, and labeled for treatment of an indicated condition. 10 [00351] As disclosed herein, the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the 15 individual conditions of a patient. A specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease. The appropriate dose and dosage times under certain conditions can be determined by the test based 20 on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques. 25 [00352] Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD5 0 (the dose lethal to 50% of the population) and the ED 5 o (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the 30 therapeutic index and it can be expressed as the ratio ED 5 o/LDso. Compositions that exhibit large therapeutic indices are preferred. 155 WO 2005/082856 PCT/GB2005/000717 EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS [00353] With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, 5 capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and additional routes. Representative pharmaceutical compositions follow. (a) Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques. 10 (b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature. (c) For parental (including intravenous and subcutaneous) sterile 15 solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility. 20 [00354] Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art. FORMULATION EXAMPLES 25 [00355] The following examples are again given by way of illustration only and are not to be construed as limiting. EXAMPLE 1 Tablet Formulation A suitable formulation for a tablet containing 10 milligrams of active 30 ingredient is as follows: 156 WO 2005/082856 PCT/GB2005/000717 mg Active Ingredient 10 Lactose 61 Microcrystalline Cellulose 25 Talcum 2 Magnesium stearate 1 Colloidal silicon dioxide 1 EXAMPLE 2 Tablet Formulation 5 Another suitable formulation for a tablet containing 100 mg is as follows: mg Active Ingredient 100 Polyvinylpyrrolidone, crosslinked 10 Potato starch 20 Polyvinylpyrrolidone 19 Magnesium stearate 1 Microcrystalline Cellulose 50 Film coated and colored. The film coating material consists of: Hypromellose 10 Microcryst. Cellulose 5 Talcum 5 157 WO 2005/082856 PCT/GB2005/000717 Polyethylene glycol 2 Color pigments 5 EXAMPLE 3 Capsule Formulation A suitable formulation for a capsule containing 50 milligrams of active 5 ingredient is as follows: mg Active Ingredient 50 Corn starch 26 Dibasic calcium phosphate 50 Talcum 2 Colloidal silicon dioxide 2 filled in a gelatin capsule. EXAMPLE 4 10 Solution for injection A suitable formulation for an injectable solution is as follows: Active Ingredient mg 10 Sodium chloride mg q.s. Water for Injection mL add 1.0 EXAMPLE 5 15 Liquid oral formulation 158 WO 2005/082856 PCT/GB2005/000717 A suitable formulation for 1 liter of a an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: mg Active Ingredient 2 Saccharose 250 Glucose 300 Sorbitol 150 Orange flavor 10 Colorant q.s. Purified water add 1000 mL 5 EXAMPLE6 Liquid oral formulation Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows: G Active Ingredient 20.00 Tragacanth 7.00 Glycerol 50.00 Saccharose 400.00 Methylparaben 0.50 Propylparaben 0.05 Black currant-flavor 10.00 159 WO 2005/082856 PCT/GB2005/000717 Soluble Red color 0.02 Purified water add 1000 mL EXAMPLE 7 Liquid oral formulation Another suitable formulation for 1 liter of a liquid mixture containing 2 5 milligrams of active ingredient in one milliliter of the mixture is as follows: G Active Ingredient 2 Saccharose 400 Bitter orange peel tincture 20 Sweet orange peel tincture 15 Purified water add 1000 mL EXAMPLE 8 Aerosol formulation 10 180 g aerosol solution contain: G Active Ingredient 10 Oleic acid 5 Ethanol 81 Purified Water 9 Tetrafluoroethane 75 160 WO 2005/082856 PCT/GB2005/000717 15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar. EXAMPLE 9 5 TDS formulation 100 g solution contain: G Active Ingredient 10.0 Ethanol 57.5 Propyleneglycol 7.5 Dimethylsulfoxide 5.0 Hydroxyethylcellulose 0.4 Purified water 19.6 1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before 10 use. EXAMPLE 10 Nanoparticle formulation 10 g of polybutylcyanoacrylate nanoparticles contain: 15 G Active Ingredient 1.00 Poloxamer 0.10 161 WO 2005/082856 PCT/GB2005/000717 Butylcyanoacrylate 8.75 Mannitol 0.10 Sodium chloride 0.05 Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under 5 vacuum. PHARMACOLOGY - SUMMARY [00356] The active principles of the present invention, and pharmaceutical compositions thereof and method of treating therewith, are 10 characterized by unique and advantageous properties, rendering the "subject matter as a whole", as claimed herein, unobvious. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics: 15 METHODS BINDING ASSAYS FOR THE CHARACTERIZATION OF MGLUR5 ANTAGONIST PROPERTIES 20 [2H]MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to transmembrane allosteric modulatory sites of mGIuR5 receptors in cortical membranes Preparation of rat cortical membranes: 25 [00357] Male Sprague-Dawley rats (200-250 g) are decapitated and their brains are removed rapidly. The cortex is dissected and homogenized in 20 volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000xg for 10 min. The pellet is discarded 162 WO 2005/082856 PCT/GB2005/000717 and the supernatant centrifuged at 20,000xg for 20 min. The resulting pellet is re-suspended in 20 volumes of distilled water and centrifuged for 20 min at 8000xg. Then the supernatant and the buffy coat are centrifuged at 48,000xg for 20 min in the presence of 50 mM Tris-HCI, pH 8.0. The pellet is 5 then re-suspended and centrifuged two to three more times at 48,000xg for 20 min in the presence of 50 mM Tris-HCI, pH 8.0. All centrifugation steps are carried out at 4 0 C. After resuspension in 5 volumes of 50 mM Tris-HCI, pH 8.0 the membrane suspension is frozen rapidly at -80'C. 10 [00358] On the day of assay the membranes are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 8.0 and centrifugation at 48,000xg for 20 min. and finally re-suspended in 50 mM Tris-HCl, pH 7.4. The amount of protein in the final membrane preparation (250-500 pg/ml) is determined according to the method of Lowry (Lowry 0. H. et al., 1951. J. 15 Biol. Chem. 193, 256-275).
[
3 H]MPEP Assay [00359] Incubations are started by adding ( 3 H)-MPEP (50.2 Ci/mmol, 5nM, Tocris) to vials with 125-250pg protein (total volume 0.5 ml) and 20 various concentrations of the agents. The incubations are continued at room temperature for 60 min (equilibrium was achieved under the conditions used). Non-specific binding is defined by the addition of unlabeled MPEP (10 pM). Incubations are terminated using a Millipore filter system. The samples are rinsed twice with 4 ml of ice cold assay buffer over glass fibre filters 25 (Schleicher & Schuell) under a constant vacuum. Following separation and rinse, the filters are placed into scintillation liquid (5 ml Ultima Gold) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Hewlett Packard, Liquid Scintillation Analyser). 30 Characterization [00360] Specific binding is extremely high i.e. normally > 85% and essentially independent of buffer (Tris or HEPES oth 50 mM) and pH (6.8 8.9). There is a clear saturable protein dependence and the chosen protein concentration used for subsequent assays (250-500 pg/mI) is within the 163 WO 2005/082856 PCT/GB2005/000717 linear portion of this dependence. Cold MPEP displaces hot ligand with an ICso of 18.8 ± 4.1nM. The Kd of ( 3 H)-MPEP of 13.6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of displacers as Kd values (IC 50 of cold MPEP equates 5 to a Ki of 13.7 nM). Bma was 0.56 pm / mg protein. Compounds of the present invention exhibit specific affinity for transmembrane modulatory sites of mGLuR5 receptors in cortical/cerebellar membrane preparations. FUNCTIONAL ASSAY OF MGLURI RECEPTORS IN CEREBELLAR 10 GRANULE CELLS - RADIOACTIVE ASSAY FOR CHANGES IN IP3 LEVELS Preparation of cerebellar granule cells [00361] Cerebellar cortici are obtained from P8 postnatal Sprague 15 Dawley rats, mechanically disrupted into small pieces with forceps and then transferred to Ca 2 + and Mg 2 + free Hank's buffered salt solution (HBSS-CMF) on ice. After three washes in HBSS-CMF, the tissue pieces are incubated 370C for 8 minutes in the presence of 0.25% trypsin / 0.05% DNase. The enzymatic reaction is stopped with 0.016% DNAase / 0.1% ovomucoid 20 before centrifugation at 800 rpm for 5 minutes. The supernatant is replaced twice with NaHCO 3 /HEPES-buffered basal Eagle medium (BME) plus 20 mM KCl. Cells are mechanically dissociated in 2 ml of BME by trituration through three Pasteur pipettes of successively decreasing tip diameter and then filtered through a 48 pM gauge filter. Cells are plated at a density of 25 150,000 cells in 50 pl in each well of poly-L-Lysin pre-coated 96 well plates (Falcon). The cells are nourished with BEM supplemented with 10% foetal calf serum, 2mM glutamine (Biochrom), 20 mM KCI and gentamycin (Biochrom) and incubated at 36*C with 5%CO2 at 95% humidity. After 24 h, cytosine-R-D-arabinofuranoside (AraC, 10 pM) is added to the medium. 30
IP
3 assay with [ 3 H]myo-inositol [00362] After 6 DIV the culture medium is replaced completely with inositol free DMEM (ICN) containing [ 3 H]myo-inositol (Perkin Elmer) at a final concentration of 0.5 pCi / 100 pl / well and incubated for a further 48 hours. 164 WO 2005/082856 PCT/GB2005/000717 The culture medium in each well is replaced with 100pL Locke's buffer (contains in (mM) NaCl (156), KCI (5.6), NaHCO 3 (3.6), MgC1 2 (1.0), CaC 2 (1.3), Glucose (5.6), HEPES (10)) with additional (20 mM Li, pH 7.4) and incubated for 15 min at 37*C. Locke's buffer is replaced with agonists / 5 agonists / putative mGluR1 ligands in Locke's buffer and incubated for 45 min. These solutions are then replaced by 100 pL 0.1 M HCI in each well and incubated for a further 10 mins on ice. The 96 well plates can be frozen at 20*C at this stage until further analysis. 10 (00363] Home made resin exchange columns are prepared as follows. Empty Bio-Spin Chromatography columns (Biorad) are plugged with filter paper before filling with 1.1-1.2 ml of resin (AG1-X8 Biorad, 140-14444) suspended in 0.1 M formic acid (24 g resin per 50 ml acid). The formic acid is allowed to run out before sealing the syringe tips and filling with 200-300 pL 15 of 0.1M formic acid before storage at 4 0 C. On the day of assay, columns are washed with 1 ml of 0.1M formic acid followed by I ml of distilled water. The contents of each assay well are then added to one column and washed with 1 ml distilled water followed by I ml of 5 mM sodium tetraborate / 60 mM sodium formate. The retained 20 radioactive inositol phosphates are then eluted with 2 * 1ml of IM ammonium formate / 0.1M formic acid into 24-well visiplates. Scintillation liquid (1.2 ml UltimaFlow AF) is added to each well and the plate sealed and vortexed before radioactivity is determined by conventional liquid scintillation counting (Microbeta,Perkin Elmer). Unless otherwise stated, all reagents are 25 obtained from Sigma. [00364] Compounds of the present invention have an IC 5 o range of about 0.5 nM to about 100 p-M (B-IC 5 o). 30 CONCLUSIONS [00365] In conclusion, from the foregoing, it is apparent that the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the 165 WO 2005/082856 PCT/GB2005/000717 active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith, all possessed of the foregoing more specifically enumerated characteristics and advantages. 5 [00366] The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been 10 completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies, such as the U.S. Federal Food and Drug Administration, which are responsible for and 15 authorized to pass judgment on such questions. [00367] The instant tetrahydroquinolinones derivatives represent a novel class of Group I mGluR antagonists. In view of their potency, they will be useful therapeutics in a wide range of CNS disorders which involve 20 excessive glutamate induced excitation. [00368] These compounds accordingly find application in the treatment of the following disorders of a living animal body, especially a human: AIDS related dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, 25 bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving B-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivoponto-cerebellar atrophy, 30 Parkinson's disease, vascular and frontal lobe dementia, eye injuries (e.g. glaucoma, retinopathy), head and spinal cord injuries, trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), convulsions, glioma 166 WO 2005/082856 PCT/GB2005/000717 and other tumours, inner ear insult (e.g. in tinnitus, sound or drug-induced), L-dopa-induced and tardive dyskinesias. [00369] These compounds also find application in the treatment of the 5 following disorders of a living animal body, especially a human: addiction (nicotine, alcohol, opiate, cocaine, amphetamine obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome and hyperactive children, autism, convulsions / epilepsy, dementia (e.g. in Alzheimer's 10 disease, Korsakoff syndrome, vascular dementia, HIV infections), depression (including that resulting from Borna virus infection) and bipolar manic-depressive disorder, drug tolerance e.g. to opioids, dyskinesia (e.g. L Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, 15 multiple sclerosis, muscle spasms, pain (chronic and acute), Parkinson's disease, schizophrenia, spasticity, tinnitus, Tourette's syndrome, urinary incontinence and vomiting. [00370] The method-of-treating a living animal body with a compound 20 of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated. 25 [00371] Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with an Group I mGluR antagonist, is carried out in the usual manner comprising the step of 30 admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament. 167 WO 2005/082856 PCT/GB2005/000717 [00372] Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, 5 liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing. 10 [00373] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. 15 [00374] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference. 168

Claims (88)

  1. 2-Benzyloxy-7,8-dihydro-6H-quinoline-5-one, 2-Phenoxy-7,8-dihydro-6H 5 quinolin-5-one, 2-(1H-Indol-3-yl)-7,8-dihydro-6H-quinolin-5-one, 2-(1H-Indol
  2. 3-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Thiophen-2-yl-7,8 dihydro-6H-quinolin-5-one, 2-Ethoxy-7,8-dihydro-6H-quinolin-5-one, 7,7 Dimethyl-2-(6-methyl-pyridin-3-ylmethylsulfanyl)-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile, 2-(1 H-Benzoimidazol-2-ylmethylsulfanyl)-7,7 10 dim ethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbon itri le, 2-(4-Methoxy phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-(4-Chloro-phenyl)-7,7-dimethyl-7,8 dihydro-6H-quinolin-5-one, 2-(4-Fluoro-phenyl)-7,8-dihydro-6H-quinolin-5 one, 2-(4-isopropyl-phenyl)-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, or 2-Cyclohexyl-7,8-dihydro-6H-quinolin-5-one. 15 2. A compound of Claim 1, wherein R 3 represents hydrogen, cyano or nitro. 3. A compound of Claim 1, wherein R 4 represents hydrogen. 20
  3. 4. A compound of Claim 1, wherein R 5 and R 6 , which may be the same or different, each independently represent hydrogen or C 1 . 6 alkyl, and R' and R3, which may be the same or different, each independently represent hydrogen, C 1 . 6 alkyl or cycIoC 3 . 12 alkyl, or wherein one of R 5 and R 6 and one 25 of R 7 and R 8 together represent -(CH 2 )n- with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R and R are both hydrogen, or wherein R 7 and R3 may together represent -(CH 2 )m- with m being 4, 5 or 6.
  4. 5. A compound of Claim 4, wherein R 5 and R 6 , which may be the same or 30 different, each independently represent hydrogen, methyl, or ethyl.
  5. 6. A compound of Claim 4, wherein R 7 and R 8 , which may be the same or different, each independently represent hydrogen, methyl, or cyclohexyl. 172 WO 2005/082856 PCT/GB2005/000717
  6. 7. A compound of Claim 4, wherein one of R 5 and R 6 and one of R 7 and R 8 together represent -(CH 2 )n- with n being 4, while the remaining of R 5 and RI as well as R 7 and R" are both hydrogen. 5 8. A compound of Claim 4, wherein R 7 and R 8 together represent -(CH 2 )m- with m being 5 or 6.
  7. 9. A compound of Claim 1, wherein R 9 and R 1 0 , which may be the same or different, each independently represent hydrogen or C 1 .salkyl. 10
  8. 10. A compound of Claim 9, wherein R 9 and R1 0 , which may be the same or different, each independently represent hydrogen or methyl.
  9. 11. A compound of Claim 1, wherein R 2 represents C 1 - 6 alkylthio, C 4 . 6 15 alkenylthio or cycloC 3 - 1 2 alkylthio.
  10. 12. A compound of Claim 11, wherein R 3 represents hydrogen or cyano; R 4 represents hydrogen, halogen, nitro or C 1 . 6 alkoxy; 20 R 5 and R 6 , which may be the same or different, each independently represent hydrogen or C 1 . 6 alkyl; R 7 and R3, which may be the same or different, each independently represent hydrogen, C 1 . 6 alkyl or cycIoC3. 12 alkyl or R 7 and R3 may together represent -(CH 2 )m- with m being 4, 5 or 6; and 25 R 9 and R 10 , which may be the same or different, each independently represent hydrogen or C1. 6 alkyl.
  11. 13. A compound of Claim 12, wherein R 3 represents cyano. 30 14. A compound of Claim 12, wherein R 4 represents hydrogen.
  12. 15. A compound of Claim 12, wherein R 5 and R, which may be the same or different, each independently represent hydrogen, methyl, or ethyl. 173 WO 2005/082856 PCT/GB2005/000717
  13. 16. A compound of Claim 12, wherein R and R 8 , which may be the same or different, each independently represent hydrogen, methyl, or cyclohexyl.
  14. 17. A compound of Claim 12, wherein R 7 and R8 together represent 5 -(CH 2 )m- with m being 5 or 6.
  15. 18. A compound of Claim 12, wherein R 9 and R 10 , which may be the same or different, each independently represent hydrogen or methyl. 10 19. A compound of Claim 1, wherein R 2 represents C 2 . 6 alkoxy, cycloC 3 .. 12 alkoxy, cycloC 3 - 12 alkyl-C 1 . 6 alkoxy, aryloxy, aryl-C 1 . 6 alkoxy or C1. 6 alkoxy-C 1 . 6 alkyl.
  16. 20. A compound Claim 19, wherein 15 R 3 represents hydrogen or cyano; R 4 represents hydrogen, halogen, nitro or C 1 . 6 alkoxy; R 5 and R 6 , which may be the same or different, each independently represent hydrogen or C 1 . 6 alkyl; R 7 and R3, which may be the same or different, each independently 20 represent hydrogen, C 1 .. 6 alkyl or cycloC 3 - 12 alkyl or R 7 and R 8 may together represent -(CH 2 )m- with m being 4, 5 or 6; and R 9 and R1 0 , which may be the same or different, each independently represent hydrogen or C1.. 6 alkyl. 25 21. A compound of Claim 20, wherein R 3 represents cyano.
  17. 22. A compound of Claim 20, wherein R 4 represents hydrogen.
  18. 23. A compound of Claim 20, wherein R5 and R , which may be the same 30 or different, each independently represent hydrogen, methyl, or ethyl.
  19. 24. A compound of Claim 20, wherein R 7 and R 8 , which may be the same or different, each independently represent hydrogen, methyl, or cyclohexyl. 174 WO 2005/082856 PCT/GB2005/000717
  20. 25. A compound of Claim 20, wherein R 7 and R3 together represent -(CH 2 )m- with m being 5 or 6.
  21. 26. A compound of Claim 20, wherein R 9 and R 10 , which may be the same 5 or different, each independently represent hydrogen or methyl.
  22. 27. A compound of Claim 1, wherein R 2 represents C 16 -alkylamino, di-C1.ealkylamino, cycloC3- 12 alkylamino, cycloC 3 -1 2 alkyl-C 1 . 6 alkylamino, di-C 1 . 6 alkylamino-C 6 alkyl, C 1 - 6 alkoxy-C 2 - 6 alkylamino, arylamino, arylC 1 . 6 10 alkylamino, N-cycloC 3 . 12 alkyl-N-C 1 . 6 alkylamino, N-aryl-N-C 1 .ealkylamino, N-aryl-C1. 6 alkyl-N-C1.6alkylamino, wherein the aryl moieties may be unsubstituted or substituted by one or two substituents, each independently selected from methoxy, cyano, halogen, hydroxy, methyl, pyridyl, morpholinyl and piperidinyl. 15
  23. 28. A compound of Claim 27, wherein R 3 represents hydrogen or cyano; R 4 represents hydrogen, halogen, nitro or C 1 .salkoxy; R 5 and R 6 , which may be the same or different, each independently 20 represent hydrogen or C 1 . 6 alkyl; R 7 and R 8 , which may be the same or different, each independently represent hydrogen, C 1 . 6 alkyl or cycloC 3 . 12 alkyl, or R 7 and R8 may together represent -(CH 2 )m- with m being 4, 5 or 6; and R 9 and R1 0 , which may be the same or different, each independently 25 represent hydrogen or C 1 . 6 alkyl.
  24. 29. A compound of Claim 28, wherein R 3 represents cyano.
  25. 30. A compound of Claim 28, wherein R 4 represents hydrogen. 30
  26. 31. A compound of Claim 28, wherein R 5 and R 6 , which may be the same or different, each independently represent hydrogen, methyl, or ethyl. 175 WO 2005/082856 PCT/GB2005/000717
  27. 32. A compound of Claim 28, wherein R and R 8 , which may be the same or different, each independently represent hydrogen, methyl, or cyclohexyl.
  28. 33. A compound of Claim 28, wherein R 7 and R 8 together represent 5 -(CH 2 )m- with m being 5 or 6.
  29. 34. A compound of Claim 28, wherein R 9 and R 1 0 , which may be the same or different, each independently represent hydrogen or methyl. 10 35. A compound of Claim 1, wherein R 2 represents C 2 - 6 alkyl, cycloC 3 .. 1 2 alkyl, cycloC 3 . 1 2 alkyl-C 1 . 6 alkyl, C 2 . 6 alkenyl or aryl-Ci 6 alkyl.
  30. 36. A compound of Claim 35, wherein R 2 represents adamantyl. 15 37. A compound of Claim 35, wherein R 3 represents hydrogen, cyano, nitro or morpholino; R 4 represents hydrogen, halogen, nitro or C 1 . 6 alkoxy; R 5 and R 6 , which may be the same or different, each independently represent hydrogen or C 1 .ealkyl; 20 R 7 and R 8 , which may be the same or different, each independently represent hydrogen, C 1 . 6 alkyl or cycloC 3 .. 12 alkyl, or R 7 and R may together represent -(CH 2 )m- with m being 4, 5 or 6; and R 9 and R 1 0 , which may be the same or different, each independently represent hydrogen or C 1 .ealkyl. 25
  31. 38. A compound of Claim 37, wherein R 3 represents hydrogen, cyano, or nitro.
  32. 39. A compound of Claim 37, wherein R 4 represents hydrogen. 30
  33. 40. A compound of Claim 37, wherein R 5 and R , which may be the same or different, each independently represent hydrogen, methyl, or ethyl. 176 WO 2005/082856 PCT/GB2005/000717
  34. 41. A compound of Claim 37, wherein R 7 and R , which may be the same or different, each independently represent hydrogen, methyl, or cyclohexyl.
  35. 42. A compound of Claim 37, wherein R 7 and R 8 together represent 5 -(CH 2 )m- with m being 5 or 6.
  36. 43. A compound of Claim 37, wherein R 9 and R1 0 , which may be the same or different, each independently represent hydrogen or methyl. 10 44. A compound of Claim 1, wherein R 2 represents aryl-C 2 . 6 alkynyl or heteroary-C 2 . 6 alkynyl, wherein the aryl moiety may be unsubstituted or substituted by one or two substituents each independently selected from,methoxy, cyano, halogen, hydroxy and methyl and the heteroaryl moiety may be unsubstituted or substituted by one or two substituents 15 each independently selected from phenyl, methoxy, cyano, halogen, hydroxy and methyl.
  37. 45. A compound of Claim 44, wherein the aryl and/or heteroaryl moiety is substituted at the meta position. 20
  38. 46. A compound of Claim 44, wherein R 3 represents hydrogen, cyano or nitro; R 4 represents hydrogen; R5 and R 6 , which may be the same or different, each independently 25 represent hydrogen or C 1 . 6 alkyl; R 7 and R 8 , which may be the same or different, each independently represent hydrogen, C 1 . 6 alkyl or cycloC 3 -1 2 alkyl, or R 7 and Ra may together represent -(CH 2 )m- with m being 4, 5 or 6; and R 9 and R 1 0 , which may be the same or different, each independently 30 represent hydrogen or C 1 . 6 alkyl.
  39. 47. A compound of Claim 46, wherein R represents hydrogen or cyano.
  40. 48. A compound of Claim 46, wherein R 4 represents hydrogen. 177 WO 2005/082856 PCT/GB2005/000717
  41. 49. A compound of Claim 46, wherein R 5 and R 6 , which may be the same or different, each independently represent hydrogen or methyl. 5 50. A compound of Claim 46, wherein R and R 8 , which may be the same or different, each independently represent hydrogen, methyl, or cyclohexyl.
  42. 51. A compound of Claim 46, wherein R 7 and R 8 together represent -(CH 2 )m- with m being 5 or 6. 10
  43. 52. A compound of Claim 46, wherein R 9 and R 10 , which may be the same or different, each independently represent hydrogen or methyl.
  44. 53. A compound of Claim 1, wherein R 2 represents biaryl or heteroaryl-aryl, 15 wherein the aryl moieties may be unsubstituted or substituted by one or two substituents each independently selected from methoxy, cyano, halogen, hydroxy and methyl.
  45. 54. A compound of Claim 53, wherein R 2 represents heteroaryl-aryl, 20 wherein the heteroaryl moiety is selected from pyridyl, pyrimidyl, oxazolyl, oxadiazolyl, thiazolyl and imidazolyl.
  46. 55. A compound of Claim 53, wherein the aryl moiety is substituted in the meta position. 25
  47. 56. A compound of Claim 53, wherein R 3 represents hydrogen, cyano or nitro; R 4 represents hydrogen; R and R 6 , which may be the same or different, each independently 30 represent hydrogen or C 1 .salkyl; R 7 and R3, which may be the same or different, each independently represent hydrogen, C 1 . 6 alkyl or cycloC 3 -1 2 alkyl, or R 7 and Re may together represent -(CH 2 )m- with m being 4, 5 or 6; and 178 WO 2005/082856 PCT/GB2005/000717 R 9 and R"', which may be the same or different, each independently represent hydrogen or CI 6 alkyl.
  48. 57. A compound of Claim 56, wherein R 3 represents hydrogen or cyano. 5
  49. 58. A compound of Claim 56, wherein R 4 represents hydrogen.
  50. 59. A compound of Claim 56, wherein R 5 and R , which may be the same or different, each independently represent hydrogen or methyl. 10
  51. 60. A compound of Claim 56, wherein R 7 and R3, which may be the same or different, each independently represent hydrogen, methyl, or cyclohexyl.
  52. 61. A compound of Claim 56, wherein R 7 and Ra together represent 15 -(CH 2 )m- with m being 5 or 6.
  53. 62. A compound of Claim 56, wherein R 9 and R 10 , which may be the same or different, each independently represent hydrogen or methyl. 20 63. A compound of Claim 1, wherein R 2 represents aryl-heteroaryl or heteroaryl-heteroaryl, wherein the aryl moieties and the heteroaryl moieties that are not directly attached to the tetrahydroquinoline ring of formula IA may be unsubstituted or substituted by one or two substituents each independently selected from methoxy, cyano, halogen, hydroxy, methyl, 25 pyridyl, morpholinyl and piperidinyl.
  54. 64. A compound of Claim 63, wherein the heteroaryl moiety is selected from pyridyl, pyrimidyl, oxazolyl, oxadiazolyl, thiazolyl and imidazolyl. 30 65. A compound of Claim 63, wherein the aryl and/or heteroaryl moiety is substituted in the meta position.
  55. 66. A compound of the Claim 63, wherein R 3 represents hydrogen, cyano or nitro; 179 WO 2005/082856 PCT/GB2005/000717 R 4 represents hydrogen; R 5 and R , which may be the same or different, each independently represent hydrogen or C 1 . 6 alkyl; R 7 and R8, which may be the same or different, each independently 5 represent hydrogen, C 1 . 6 alkyl or cycloC 3 - 1 2 alkyl or R and R3 may together represent -(CH 2 )m- with m being 4, 5 or 6; and R 9 and R 10 , which may be the same or different, each independently represent hydrogen or C 1 . 6 alkyl. 10 67. A compound of Claim 66, wherein R 3 represents hydrogen or cyano.
  56. 68. A compound of Claim 66, wherein R 4 represents hydrogen.
  57. 69. A compound of Claim 66, wherein R 5 and R 6 , which may be the same 15 or different, each independently represent hydrogen or methyl.
  58. 70. A compound of Claim 66, wherein R and R 8 , which may be the same or different, each independently represent hydrogen, methyl, or cyclohexyl. 20 71. A compound of Claim 66, wherein R 7 and R3 together represent -(CH 2 )m- with m being 5 or 6.
  59. 72. A compound of Claim 66, wherein R 9 and R 10 , which may be the same or different, each independently represent hydrogen or methyl. 25
  60. 73. A compound of Claim 1, wherein one of R 5 and R 6 and one of R7 and R 8 together represent -(CH 2 )n- with n being 3, 4 or 5, while the remaining of R 5 and R as well as R and R are both hydrogen, and wherein R 2 represents halogen, aryl, heteroaryl, arylamino, aryl-C 1 ..alkylamino, cycloC3. 30 12 alkyl, piperidino, 4-arylpiperidino, morpholino, piperazino, 4-C 1 . 6 alkylpiperazino, or 4-arylpiperazino, wherein the aryl moieties and the heteroaryl moieties may be unsubstituted or substituted by one or two substituents, each independently selected from methoxy, cyano, halogen, hydroxy and methyl. 180 WO 2005/082856 PCT/GB2005/000717
  61. 74. A compound of Claim 73, wherein the aryl and/or heteroaryl moiety is substituted in the meta position. 5 75. A compound of Claim 73, wherein R 2 represents phenylamino, phenylethylamino, adamantyl, 4-phenylpiperidino, or 4-phenylpiperazino, wherein the phenyl moiety may be unsubstituted or substituted by one or two substituents, each independently selected from methoxy, cyano, halogen, hydroxyl and methyl. 10
  62. 76. A compound of Claim 73, wherein n is 4.
  63. 77. A compound of Claim 73, wherein R 3 represents hydrogen, cyano or nitro; 15 R 4 represents hydrogen; and R 9 and R 10 , which may be the same or different, each independently represent hydrogen or C 1 . 6 alkyl.
  64. 78. A compound of Claim 77, wherein R 3 represents hydrogen or cyano. 20
  65. 79. A compound of Claim 77, wherein R 4 represents hydrogen.
  66. 80. A compound of Claim 77, wherein R 9 and R 10 , which may be the same or different, each independently represent hydrogen. 25
  67. 81. A compound of Claim 1, which is selected from: 7,7-Dimethyl-2-(2-methyl-allylsulfanyl)-5-oxo-5,6,7,8 tetrahydroquinoline-3-carbonitrile, 2-lsopropylsulfanyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3 30 carbonitrile, 7,7-Dimethyl-5-oxo-2-propylsulfanyl-5,6,7,8-tetrahydroquinoline-3 carbonitrile, 2-(2-Methyl-allylsulfanyl)-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 181 WO 2005/082856 PCT/GB2005/000717 2-Butylsulfanyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3 carbonitrile, 2-Isobutyisulfanyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3 carbonitrile, 5 2-Benzylsulfanyl-7,7-dimethyl-3-nitro-7,8-dihydro-6H-quinolin-5-one, and 2-Benzylsulfanyl-3-chloro-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, and optical isomers, polymorphs and pharmaceutically-acceptable acid 10 and base addition salts, hydrates, and solvates thereof.
  68. 82. A compound of Claim 1, which is selected from: 2-Cyclohexyloxy-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Isobutoxy-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-one, 15 2-Benzyloxy-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Benzyloxy-7-(4-chloro-phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-Isobutoxy-7-phenyl-7,8-dihydro-6H-quinolin-5-one, 2-Phenoxy-7-phenyl-7,8-dihydro-6H-quinolin-5-one, 2-Benzyloxy-7,7-pentamethylene- 7 ,8-dihydro-6H-quinoline-5-one, 20 2-Ethoxy-7,7-pentamethylene-7,8-dihydro-6H-quinoline-5-one, 2-(2-Hydroxyethoxy)-1 -yl-7,7-pentamethylene-7,8-dihydro-6H quinoline-5-one, 2-Benzyloxy-7-ethyl-7,8-dihydro-6H-quinolin-5-one, and 2-Ethoxy-7-furan-2-y-7,8-dihydro-6H-quinolin-5-one, 25 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  69. 83. A compound of Claim 1, which is selected from: 30 2-Biphenyl-4-yl-7,8-dihydro-6H-quinolin-5-one, 2-Biphenyl-4-yl-5-oxo-5, 6 ,7,8-tetrahydro-quinoline-3-carbonitrile, 2-(3-Methoxy-4-pyridin-3-yl-phenyl)-7,8-dihydro-6H-quinolin-5-one, and 2-(3-Methoxy-4-pyridin-2-yl-phenyl)- 7 ,8-dihydro-6H-quinolin-5-one, 182 WO 2005/082856 PCT/GB2005/000717 and optical isomers polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof. 5 84. A compound of Claim 1, which is selected from: 5-Oxo-2-(5-phenyl-thiophen-2-yl)-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 2-(5-m-Tolyl-thiazol-2-yl)-7,8-dihydro-6H-quinolin-5-one, 2-[5-(3-Hydroxy-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5-one, 10 2-[5-(3-Methoxy-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5-one, 2-[5-(3-Fluoro-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5-one, 2-[5-(3-Chloro-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5-one, 2-[5-(3-Bromo-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin-5-one, 2-[5-(3,5-Dimethoxy-phenyl)-thiazol-2-y]-7,8-dihydro-6H-quinolin-5 15 one, 2-[5-(3-Fluoro-5-methyl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H-quinolin 5-one, 2-[5-(3-Fluoro-5-methoxy-phenyl)-thiazol-2-yl]-7,8-dihydro-6H quinolin-5-one, 20 2-[5-(3-Fluoro-5-pyridin-2-yl-phenyl)-thiazol-2-yI]-7,8-dihydro-6H quinolin-5-one, 2-[5-(3-Fluoro-5-pyridin-3-yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H quinolin-5-one, 2-(3-Methoxy-4-pyridin-3-yl-phenyl)-7,7-dimethyl-7,8-dihydro-6H 25 quinolin-5-one, 2-(3-Methoxy-4-pyridin-2-yl-phenyl)-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one, 2-[5-(3-Fluoro-5-pyridin-4-yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H quinolin-5-one, 30 2-[5-(3-Fluoro-5-morpholin-4-yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H quinolin-5-one, 2-[5-(3-Fluoro-5-piperidin-1 -yl-phenyl)-thiazol-2-yl]-7,8-dihydro-6H quinolin-5-one, 7,7-Dimethyl-2-(5-m-tolyl-thiazol-2-yl)-7,8-dihydro-6H-quinolin-5-one, 183 WO 2005/082856 PCT/GB2005/000717 2-f 5-(3-Hydroxy-phenyl)-thiazol-2-yl-71 7-dimethyl-7, 8-dihydro-6H quinolin-5-one, 2-f 5-(3-Methoxy-phenyl)-thiazo-2-yli-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one, 5 2-[5-(3-Fluoro-phenyl)-thiazol-2-yIII-7 7 7-dimethyl-7, 8-dihydro-6H quinofin-5-one, 2-[5-(3-Chloro-phenyl)-thiazol-2-yII-7 7 7-dimethyl-7, 8-d ihydro-6H quinolin-5-one, 2-[5-(3-B romo-phenyl)-thiazol-2-yII-7 ,7-d im ethyl-7, 8-d ihydro-6H 10 quinolin-5-one, 2-[5-(3 ,5-Dimethoxy-phenyl)-thiazol-2-yl]-7,7-dim ethyl-7, 8-dihydro-6H quinolin-5-one, 2-f 5-(3-Fluoro-5-m ethyl-phenyl)-thiazol-2-YII-7,7-d im ethyl-7, 8-dihydro 6H-quinolin-5-one, 15 2-[5--(3-Flur-hnl4 iz -- l-,-iyr-6 -unln5oe 2-[5-(3-Fluoro-5-methoxy-phel)-thiazol-2-yl- 7 7-dimethyl-7, 8 dihydro-6H-quinolifl-5-ofle, 2-5(-loo5prdn2ylpey)tizl2y 77-dim ethyl-7, 8 dihydro-6H-quinolifl-5-ofle, 20 2-[5-(3-F Iuoro-5-pyridin-3-yl-pheflyl)-thiazoI-2-yl]-7,7-dim ethyl-7, 8 dihydro-6H-quinolin-5-ofle, 2-[5-(3-Fluoro-5-pyridin4-y-phelyl)-thiazo-2-yW] 7 , 7-dim ethyl-7, 8 dihydro-6H-quinolifl-5-ofle, 2-f 5-(3-F Iuoro-5-m orpholin-4-y-pheny)-thiazol-2-YI]- 7 ,7-dimethyl-7, 8 25 dihydro-6H-quilifl-5-ofle, 2-f 5-(3-Fluoro-5-piperidifl-1 -yl-phenyI)-thiazo-2-yII-7, 7-dimethyl-7, 8 dihydro-6H-quinolifl-5-ofle, 2-(5-m-Toly-[1,34oaizl2yl ,-iyr-H-unln5oe 2-(5-m-Tolyl-oxazoI-2-yI)- 7 , 8-dihydro-6H-quinolin-5-ofle, 30 2-(1 -m-TolyI H-imidazol-4-yi)-7 ,8-dihydro-6H-quinolin-5-ofle, 2-(5-m-ToIYI-isoxazoI-3-yi)- 7 , 8-dihydro-6H-quiflolifl-5-ofle, 2-[5-(3-Fluoro-pheflD-oxazol2yi]- 7 , 8-dihydro-6H-quinolifl-5-Qfle, 2-f I-(3-Fluoro-phenyl)-1 H-imidazol-4-y1-7, 8-dihydro-6H-quilifl-5 one, 184 WO 2005/082856 PCT/GB2005/000717 2-[5-(3-Fluoro-phenyl)-isoxazol-3-yl]-7,8-dihydro-6H-quinolin-5-one, and 5-Oxo-2-(5-phenyl-thiazol-2-yl)-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 5 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  70. 85. A compound of Claim 1, which is selected from: 10 3-[2-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-thiazol-5-yl]-benzonitrile, 3-Fluoro-5-[2-(5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-thiazol-5-yl] benzonitrile, 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-thiazol-5-yl] benzonitrile, 15 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-thiazol-5-yl] 5-fluoro-benzonitrile, 3-[2-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-oxazol-5-yl]-benzonitrile, 3-[3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-y)-isoxazol-5-yl] benzonitrile, 20 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-oxazol-5-yl] benzonitrile, 3-[3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-isoxazol-5 yl]-benzonitrile, 3-[2-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yi)-oxazol-5-yl] 25 5-fluoro-benzonitrile, 3-[3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-y)-isoxazol-5 yI]-5-fluoro-benzonitrile, 7,7-Dimethyl-2-(5-pyridin-3-yl-thiazol-2-yl)- 7 ,8-dihydro-6H-quinolin-5 one, 30 2-(5-Pyridin-3-yl-thiazol-2-y!)-7,8-dihydro-6H-quinolin-5-one, 3-[3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-yl)-isoxazol-5 yi]-benzonitrile, and 7,7-Dimethyl-5-oxo-2-(3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1 -yl) 5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 185 WO 2005/082856 PCT/GB2005/000717 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof. 5 86. A compound of Claim 1, which is selected from: 2-Phenylethynyl-7,8-dihydro-6H-quinolin-5-one, 5-Oxo-2-phenylethynyl-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 2-m-Tolylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Hydroxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 10 2-(3-Methoxy-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 2-(3-Fluoro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 2-(3-Chloro-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 2-(3-Bromo-phenylethynyl)-7,8-dihydro-6H-quinolin-5-one, 2-Phenylethynyl-6,7,8,9,9a, 1 0-hexahydro-5aH-benzo[gquinolin-5 15 one, 7,7-Dimethyl-2-pyridin-3-yiethynyl-7,8-dihydro-6H-quinolin-5-one, 7,7-Dimethyl-2-m-tolylethynyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Hydroxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 20 2-(3-Methoxy-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-(3-Fluoro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-(3-Chloro-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 25 one, 2-(3-Bromo-phenylethynyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, and 3-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl) benzonitrile, 30 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  71. 87. A compound of Claim 1, which is selected from: 186 WO 2005/082856 PCT/GB2005/000717 2-Pyridin-3-yethynyl-7,8-dihydro-6H-quinolin-5-one, 3-(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylethynyl)-benzonitrile, 2-Thiazol-5-yethynyl-7,8-dihydro-6H-quinolin-5-one, 2-Oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 5 2-(2-Pheny-oxazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 2-(2-Phenyl-thiazol-5-ylethynyl)-7,8-dihydro-6H-quinolin-5-one, 7,7-Dimethyl-2-pyridin-3-yiethynyl-7,8-dihydro-6H-quinolin-5-one, 7,7-Dimethyl-2-thiazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one, and 7,7-Dimethyl-2-oxazol-5-ylethynyl-7,8-dihydro-6H-quinolin-5-one, 10 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  72. 88. A compound of Claim 1, which is selected from: 15 7,7-Dimethyl-2-phenethyl-7,8-dihydro-6H-quinolin-5-one, 2-Benzyl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-[2-(2-Methoxyphenyl)ethyl]-7,8-dihydro-6H-quinolin-5-one, 2-Phenethyl-7,8-dihydro-6H-quinolin-5-one, 2-Cyclohexylmethyl-7,7-tetramethylene-7,8-dihydro-6H-quinolin-5 20 one, 2-Benzyl-7,7-tetramethylene-7,8-dihydro-6H-quinolin-5-one, 2-Benzyl-6-propyl- 7 ,8-dihydro-6H-quinolin-5-one, 2-Benzyl-6-ethyl-7,8-dihydro-6H-quinolin-5-one, 2-Benzyl-7-propyl- 7 ,8-dihydro-6H-quinolin-5-one, 25 2-Benzyl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Benzyl-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Benzyl-7-ethyl-7,8-dihydro-6H-quinolin-5-one, (cis, trans) 2-Benzyl-6-ethyl-8-methyl-7,8-dihydro-6H-quinolin-5-one and 2-benzyl-8-ethyl-6-methyl-7,8-dihydro- 6 H-quinolin-5-one, 30 2-Cyclohexylmethyl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Cyclohexylmethyl-7-ethyl-7,8-dihydro-6H-quinolin-5-one, 2-Cyclohexylmethyl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Cyclohexylmethyl-6-ethyl- 7 ,8-dihydro-6H-quinolin-5-one, 2-Benzyl-7,8-dihydro-6H-quinolin-5-one, 187 WO 2005/082856 PCT/GB2005/000717 7,7-Dimethyl-2-styryl-7,8-dihydro-6H -quinolin-5-one, 2-[2-(3,5-Dimethoxy-phenyl)-vinyl]-7,8-dihydro-6H-quinolin-5-one, and 2-[2-(3,5-Dimethoxy-phenyl)-vinyl]-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one, 5 2-[l-(4-Methoxy-phenyl)-piperidin-4-yl]-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile, and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof. 10
  73. 89. A compound of Claim 1, which is selected from 2-Adamantan-1-yl-6-propyl-7,8-dihydro-6H-quinolin-5-one, 2-Adamantan-1 -yl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 -one, 2-Adamantan-1 -yl-7,8-dihydro-6H-quinolin-5-one, 15 2-Adamantan-1 -yl-7,7-pentamethylene-7,8-dihydro-6H-quinoline-5 one, 2-Cyclohexyl-7-propyl-7,8-dihydro-6H-quinolin-5-one, 2-Adamantan-1 -yl-6-ethyl-8-methyl-7,8-dihydro-6 H-quinolin-5-one, 2-Adamantan-1 -yl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 20 (cis,trans) 2-Adamantan-1 -yl-6-ethyl-8-methyl-7,8-dihydro-6H quinolin-5-one and 2-adamantan-1-yl-8-ethyl-6-methyl-7,8-dihydro 6H-quinolin-5-one, 2-Cyclohexyl-7-isopropyl-7,8-dihydro-6H-quinolin-5-one, and 2-Cyclohexyl-6-ethyl-6-methyl-7,8-dihydro-6H-quinolin-5-one, 25 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  74. 90. A compound of Claim 1, which is selected from: 30 2-isopropyl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 7-(4-Dimethylamino-phenyl)-2-hexyl-7,8-dihydro-6H-quinolin-5-one, cis,trans 6-Ethyl-2-hexyl-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Hexyl-7-phenyl-7,8-dihydro-6H-quinolin-5-one, 2-Hexyl-cis,trans-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one, 188 WO 2005/082856 PCT/GB2005/000717 2-Hexyl-7-propyl-7,8-dihydro-6H-quinolin-5-one, 6-Ethyl-2-hexyl-7,8-dihydro-6H-quinolin-5-one, 2-Hexyl-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Hexyl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 5 cis, trans-8-Ethyl-2-hexyl-6-methyl-7,8-dihydro-6H-quinolin-5-one and cis, trans-6-ethyl-2-hexyl-8-methyl-7,8-dihydro-6H-quinolin-5-one, 2-Hexyl-7-isopropyl-7,8-dihydro-6H-quinolin-5-one, 2-Hexyl-7-(3-methoxy-phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-Hexyl-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 10 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  75. 91. A compound of Claim 1, which is selected from: 15 7-Phenyl-2-pyrid in-2-yl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Methoxy-phenyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, cis,trans-6-Ethyl-2-(4-m ethoxy-phenyl)-cistrans-6,8-dim ethyl-7,8 dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 20 2-(3-Methoxy-phenyl)-6-ethyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-6-methyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one, cis,trans 6-Ethyl-2-(3-methoxy-phenyl)-8-methyl-7,8-dihydro-6H quinolin-5-one and 8-ethyl-2-(3-methoxy-phenyl)-6-methyl-7,8 25 dihydro-6H-quinolin-5-one, cis 2-(3-Methoxy-phenyl)-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-6,6-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-7,7-tetramethylene-7,8-dihydro-6H-qu inolin-5 one, 30 2-(4-Methoxy-phenyl)-6-propyl-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenyl)-6-propyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Methoxy-phenyl)-6,6,8-trimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Methoxy-phenyl)-7,7-tetramethylene-7,8-dihydro-6H-quinolin-5 one, 189 WO 2005/082856 PCT/GB2005/000717 7-Ethyl-2-(4-methoxy-phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-(4-Methoxy-phenyl)-6,8-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Methoxy-phenyl)-8-methyl-6-propyl- 7 ,8-dihydro-6H-quinolin-5 one, 5 7-isopropyl-2-pyridin-3-yl-7,8-dihydro-6H-quinolin-5-one, 2-(1,3-Dihydro-isoindol-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile, and 2-(3,4-Dihydro-1 H-isoquinolin-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile, 10 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  76. 92. A compound of Claim 1, which is selected from: 15 2-Hexylamino-7,7-dimethyl-5-oxo-5, 6 , 7 ,8-tetrahydro-quinoline-3 carbonitrile, 7,7-Dimethyl-5-oxo-2-[(tetrahydro-furan-2-ylmethyl)-amino]-5,6,7,8 tetrahydro-quinoline-3-carbonitrile, 2-(2-Methoxy-ethylamino)-5-oxo-5,6,7,8-tetrahydro-quinoline-3 20 carbonitrile, 2-(Benzyl-methyl-amino)-5-oxo-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 5-Oxo-2-[(tetrahydro-furan-2-ylmethyl)-am ino]-5,6,7,8-tetrahydro quinoline-3-carbonitrile, 25 5-Oxo-2-[(pyridin-2-ylmethyl)-amino]-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 2-(Benzyl-methyl-amino)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile, 7,7-Dimethyl-5-oxo-2-[(pyridin-3-ylmethyl)-amino]-5,6,7,8-tetrahydro 30 quinoline-3-carbonitrile, 7,7-Dimethyl-2-(1 -phenyl-ethylamino)-7,8-dihydro-6H-quinolin-5-one, 2-(3,5-Dimethoxy-benzylamino)-7,8-dihydro-6H-quinolin-5-one, 2-(3,5-Difluoro-benzylamino)-7,8-dihydro-6H-quinolin-5-one, 190 WO 2005/082856 PCT/GB2005/000717 5-Oxo-2-(1 -phenyl-ethylamino)-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 2-(3-Fluoro-benzylamino)-7,8-dihydro-6H-quinolin-5-one, 2-Benzylamino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydroquinoline-3 5 carbonitrile, and 2-Benzylamino-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof. 10
  77. 93. A compound of Claim 1, which is selected from: 2-(4-Methoxy-phenylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-Phenylamino-7,8-dihydro-6H-quinolin-5-one, 15 2-(3-Methoxy-4-pyridin-2-yl-phenylamino)-7,7-dimethyl-7,8-dihydro 6H-quinolin-5-one, 2-(3-Methoxy-4-pyridin-3-yI-phenylamino)-7,7-dimethyl-7,8-dihydro 6H-quinolin-5-one, 2-(3-Fluoro-4-pyridin-2-yI-phenylamino)-7,7-dimethyl-7,8-dihydro-6H 20 quinolin-5-one, 7,7-Dimethyl-2-(pyridin-2-ylamino)-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-phenylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 2-(Indan-2-ylamino)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline 25 3-carbonitrile, 7,7-Dimethyl-5-oxo-2-phenylamino-5,6,7,8-tetrahydro-quinoline-3 carbonitrile, 2-(4-Methoxy-phenylamino)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro quinoline-3-carbonitrile, 30 2-(4-Methoxy-phenylamino)-7,7-dimethyl-3-nitro-7,8-dihydro-6H quinolin-5-one, 3-[(5-Oxo-5,6,7,8-tetrahydro-quinolin-2-ylamino)-methyl]-benzonitrile, [4-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylamino)-2 methoxy-phenyl]-acetonitrile, 191 WO 2005/082856 PCT/GB2005/000717 2-(3-Fluoro-4-pyridin-3-yl-phenylamino)-7,7-dimethyl-7,8-dihydro-6H quinolin-5-one, [4-(7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylamino)-2-fluoro phenyl]-acetonitrile, 5 2-(3-Methoxy-4-pyridin-2-yl-phenyiamino)-7,8-dihydro-6H-quinolin-5 one, 2-(3-Methoxy-4-pyridin-3-y-phenylamino)-7,8-dihydro-6H-quinolin-5 one, [2-Methoxy-4-(5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylam ino)-phenyl] 10 acetonitrile, 2-(3-Fluoro-4-pyridin-2-yl-phenylamino)-7,8-dihydro-6H-quinolin-5 one, 2-(3-Fluoro-4-pyridin-3-yl-phenylamino)-7,8-dihydro-6H-quinolin-5 one, 15 [2-Fluoro-4-(5-oxo-5,6,7,8-tetrahydro-quinolin-2-ylamino)-phenylI] acetonitrile, 7,7-Dimethyl-2-(pyridin-3-ylamino)-7,8-dihydro-6H-quinolin-5-one, 7,7-Dimethyl-2-(pyridin-4-ylamino)-7,8-dihydro-6H-quinolin-5-one, 2-(3-Methoxy-4-pyridin-2-y-phenylamino)-7,7-dimethyl-5-oxo-5,6,7,8 20 tetrahydro-quinoline-3-carbonitrile, 2-(3-Methoxy-4-pyridin-3-yl-phenylamino)-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile, 7,7-Dimethyl-5-oxo-2-(pyridin-4-ylamino)-5, 6 , 7 ,8-tetrahydro-quinoline 3-carbonitrile, 25 7,7-Dimethyl-3-nitro-2-(pyridin-4-ylamino)-7,8-dihydro-6H-quinolin-5 one, and 2-(3,5-Dimethoxy-phenylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin 5-one, 30 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  78. 94. A compound of Claim 1 which is selected from: 192 WO 2005/082856 PCT/GB2005/000717 2-Cyclopentylamino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline 3-carbonitrile, 2-Cyclohexylamino-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 2-(Adamantan-1 -ylamino)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro 5 quinoline-3-carbonitrile, 2-Cyclopentylamino-7,7-dimethyl-3-nitro-7,8-dihydro-6H-quinolin-5 one, 3-Chloro-2-cyclopentylamino-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, 10 7,7-Dimethyl-5-oxo-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7 yiamino)-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-3-nitro-7,8-dihydro-6H quinolin-5-one, 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-3-nitro-7,8-dihydro-6H 15 quinolin-5-one, 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-7,8-dihydro-6H-quinolin 5-one, 2-(4-Methoxy-cyclohexylamino)-7,7-dimethyl-5-oxo-5,6,7,8 tetrahydro-quinoline-3-carbonitrile, 20 2-(Cyclohexyl-methyl-amino)-7,8-dihydro-6H-quinolin-5-one, and 2-(Cyclohexy-methy-amino)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5 one, and optical isomers, polymorphs and pharmaceutically-acceptable acid 25 and base addition salts, hydrates, and solvates thereof.
  79. 95. A compound of Claim 1, which is selected from: 2-Azepan-1 -yl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 7,7-Dimethyi-5-oxo-2-(4-phenyl-piperazin-1-yi)-5,6,7,8-tetrahydro 30 quinoline-3-carbonitrile, 2-Azepan-1 -yl-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Phenyl-piperazin-1 -yi)-7,8-dihydro-6H-quinolin-5-one, 4-Chloro-5-oxo-2-(4-phenyI-piperazin-1 -yl)-5,6,7,8-tetrahydro quinoline-3-carbonitrile, 193 WO 2005/082856 PCT/GB2005/000717 4-Bromo-5-oxo-2-(4-phenyl-piperazin-1 -yi)- 5 , 6 , 7,8-tetrahydro quinoline-3-carbonitriie, 4-Methoxy-5-oxo-2-(4-phenyl-piperazin-1 -yI)-5,6 ,7, 8-tetrahydro quinolin e-3-carbonitrile, 5 4-Ethoxy-5-oxo-2-(4-phenyl-piperazin-1 -yi)-5,6,7, 8-tetrahydro quinoline-3-carbonitrile, 4-Ethoxy-7,7-dimethyl-5-oxo-2-(4-phenyl-piperazil-1 -yi)-5,6,7, 8 tetrahydro-quinoline-3-carbonitrile, 4-Methoxy-7,7-dimethyl-5-oxo-2-(4-pheny-piperazil-1 -yI)-5,6,7, 8 10 tetra hydro-qu inol ine-3-carbon itri le, 4-Chloro-7,7-dimethyl-5-oxo-2-(4-pheny-piperazil-1 -yi)- 5 , 6 , 7 , 8 tetra hydro-qu inoline-3-carbon itri le, 4-Braino-7, 7-dimethyl-5-oxo-2-(4-phenyl-piperaZi n-i -yi)-5, 6 , 7 , 8 tetra hydro-qu ino line-3-carbon itri le, 15 4-Bromo-7, 7-dimethyl-5-oxo-2-(4-phenyl-piperidifl-1 -yI)-5,6,7, 8 tetrahydro-quinoline-3-carbon itrile, 4-Chloro-7,7-dimethyl-5-oxo-2-(4-pheny-piperidil-1 -yI)-5,6,7, 8 tetrahydro-quinoine-3-carbonlitrile, 4-Methoxy-7 ,7-dimethyl-5-oxo-2-(4-phenyl-piperidifl-1 -yi)-5,6,7 ,8 20 tetrahydro-quino! ine-3-carbon itrile, 4-Ethoxy-7 ,7-dimethyl-5-oxo-2-(4-phely-piperidil-1 -yi)-5,6,7,8 tetrahydro-qu inoline-3-carbonitrile, 4-(2-Hydroxy-ethoxy)-7, 7-dimethyl-5-oxo-2-(4-phelYl-piPeridifl-1 -yI) 5,6,7, 8-tetrahydro-quinoline-3-carbolitrile, 25 3-Chloro-7, 7-dimethyl-2-(4-pheny-piperidil-1 -yl)-7,8-dihydro-6H quinolin-5-one, 3-B romo-7, 7-dimethyl-2-(4-phenyl-piperidifl-1 -yI)-7,8-dihydro-6H quinolin-5-one, 3-Fluoro-7, 7-dimethyl-2-(4-phenyl-piperidil-1 -yi)-7 ,8-d ihydro-6H 30 quinolin-5-one, 3-Methoxy-7, 7-dimethyl-2-(4-pheny-piperidil-1 -yi)-7,8-d ihydro-6H quinolin-5-one, 7, 7-D imethyl-3-nitro-2-(4-pheny-piperidifl-1 -yI)-7 ,8-dihydro-6H quinolin-5-one, 194 WO 2005/082856 PCT/GB2005/000717 7,7-0 imethyl-3-nitro-2-(4-phenyl-piperazin- I -yI)-7, 8-dihydro-6H quinolin-5-one, 3-Fluoro-7, 7-d imethyl-2 -(4-phenyl-piperazin-1 -yI)- 7 , 8-dihydro-6 H quinolin-5-one, 5 3-Bromo-7,7-dimethyl-2-(4-phenyl-piperazin-1 -yI)-7,8-dihydro-6H quinolin-5-one, 3-Chloro-7, 7-dimethyl-2-(4-phenyl-piperazin-1 -yI)-7, 8-d ihydro-6H quinolin-5-one,. 3-Metoxy-,7-d imethyl-2-(4-phenyl-piperazin-1 -yi)-7, 8-dihydro-6H 10 quinolin-5-one,, 2-[4-(4-Methoxy-phenyl)-piperazin-1 -yI]-7,7-dimethyl-5-oxo-5, 6,7,8 tetrahydro-qu inoline-3-carbonitrile, 2-[4-(4-F luoro-phenyl)-piperazin-1 -yi]-7,7-dim ethyl-5-oxo-5,6,7,8 tetrahydro-quino iine-3-carbonitrile, 15 341 -(5-Oxo-5,6,7, 8-tetrahydro-quinolin-2-yI)-1 H-im idazol-4-yI] benzonitrile, 3-[1 -(7,7-Dim ethyl-5-oxo-5,6,7,8-tetrahydro-quinolin-2-y)-1 H-imidazol 4-yl]-benzon itrile, 3-[l1-(7,7-Dim ethyl-5-oxo-5,6, 7,8-tetrahydro-qu inolin-2-yI)-1 H-im idazol 20 4-yI]-5-fluoro-benzonitrile, 7,7-Dimethyl-3-morpholin-4-yI-2-(4-phelyI-piperidil-1 -yi)- 7 , 8-dihydro 6H-quino [in-5-one, 7,7-Dimethyl-3-nitro-2-piperidifl-1 -yl-7,8-dihydro-6H-quinolin-5-one, 3-Chloro-7,7-dim ethyl-2-piperidin-1 -yI-7, 8-dihydro-6H-quinoaim-S-one, 25 3-Chloro-2-[4-(4-methoxy-phel)-piperazil-1 -yI]-7,7-dimethyl-7,8 dihydro-6H-quinolin-5-one, 2-[4-(4Methoxy-phenyI)-piperazin-1 -yiI- 7 , 7-dimethyl-3-nitro-7, 8 dihydro-6H-quinolin-5-one, 2-[4-(4-Methoxy-pheny)-piperidifl-1 -yI]- 7 ,7-dimethyl-5-oxo-5, 6,7,8 30 tetrahydro-quinoline-3-carbonitrile, and 7,7-Dimethy--oxo-2-piperidifl-1 -yI-5,6,7, 8-tetrahydroquinoline-3 carbonitrile, 195 WO 2005/082856 PCT/GB2005/000717 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  80. 96. A compound of Claim 1, which is selected from: 5 2-Phenylamino-6,7,8,9,9a,10-hexahydro-5aH-benzo[g]quinolin-5-one, 2-(1 -Phenyl-ethylamino)-6,7,8,9,9a, 10-hexahydro-5aH benzo[g]quinolin-5-one, 2-(Cyclohexyl-methyl-amino)-6,7,8,9,9a, 1 0-hexahydro-5aH benzo[g]quinolin-5-one, 10 2-(4-Phenyl-piperazin-I -yl)-6,7,8,99a, 1 0-hexahydro-5aH benzo[g]quinolin-5-one, 3-(5-Oxo-5,5a,6,7,8,9,9a, 1 0-octahydro-benzo[g]quinolin-2-yl) benzonitrile, 2-Pyridin-3-yl-6,7,8,9,9a, I 0-hexahydro-5aH-benzo[g]quinolin-5-one, 15 2-Piperidin-1 -yl-6,7,8,9,9a, 1 0-hexahydro-5aH-benzo[g]quinolin-5-one, and 2-Adamantan-1 -yl-6,7,8,9,9a, 1 0-hexahydro-5aH-benzo[g]quinolin-5 one, 20 and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  81. 97. A compound of Claim 1, which is 2-cyclopentylamino-7,7-dimethyl-5 oxo-5,6,7,8-tetrahydroquinoline-3-carbonitrile, optical isomers, polymorphs 25 and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  82. 98. A compound of Claim 1, which is 7,7-dimethyl-5-oxo-2-(4-phenyl piperazin-1 -yl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile, optical isomers, 30 polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof.
  83. 99. A method of treating a living animal body, including a human, afflicted with a condition associated with glutamate induced excitation of the CNS, 196 WO 2005/082856 PCT/GB2005/000717 comprising the step of administering to the living animal body, including a human, an amount of a compound of Formula IA R 4 0 R 5 5 R R 2R IA R2 N R 8 R 10 R 9 wherein 10 R 2 represents C 1 . 6 alkyl, cycIoC 3 - 12 alkyl, cycloC 3 . 12 alkyl-C 1 . 6 alkyl, C2-.alkenyl, C2- 6 alkynyl, aryl, biaryl, aryl-heteroaryl, heteroaryl heteroaryl, heteroaryl-aryl, aryl-C 1 . 6 alkyl, aryl-C 2 - 6 alkenyl, aryl C 2 - 6 alkynyl, heteroaryl, heteroaryl-C 1 . 6 alkyl, heteroaryl-C 2 . 6 alkenyl, heteroary-C 2 - 6 alkynyl, 2,3-dihydro-1 H-indenyl, C 1 . 6 alkoxy, hydroxy 15 C 2 - 6 alkoxy, cycIoC 3 - 12 alkoxy, cycIoC 3 -1 2 alkyl-C 1 .-alkoxy, aryloxy, aryl C 16 ,alkoxy, C 1 ..alkoxy-C 1 .ealkyl, C 1 .ealkylthio, C4. 6 alkenylthio, cycloC 3 -1 2 alkylthio, cycloC3..1 2 alkyl-C 1 . 6 alkylthio, cycloC 3 - 12 alkyl C 3 ,alkenylthio, C 1 . 6 alkoxy-C 1 -alkylthio, C 1 .ealkoxy-C3. 6 alkenylthio, aryl-C 1 .salkylthio, aryl-C 3 .ealkenylthio, heteroaryl-C 1 .-alkylthio, C1.6 20 alkylsulfonyl, cycloC 3 -1 2 alkyl-C 1 . 6 alkylsulfonyl, aryl-C 1 . 6 alkylsulfonyl, C 1 . 6 alkylamino, di-C 1 . 6 alkylamino, cycIoC 3 -1 2 alkylamino, C 1 .ealkoxy cycloC 3 - 1 2 alkylamino, cycloC 3 .1 2 alkyl-CI. 6 alkylamino, di-C 1 .e alkylamino-C 1 . 6 alkyl, C 1 . 6 alkoxy-C 2 . 6 alkylamino, arylamino, aryl IC 1 6 alkylamino, N-cycloC 3 - 1 2 alkyl-N-C 1 .ealkylamino, N-aryl-N 25 C 1 . 6 alkylamino, N-arylC1. 6 alkyl-N-CI 6 alkylamino, 2-indanylamino, 1,2,3,4-tetrahydroisoquinolin-2-y, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C 1 . 6 alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, 30 heteroaryl-C 1 . 6 alkoxy, heteroarylamino, heteroaryl-C 1 . 6 alkylamino, -NHC(=0)-R, -NHSO 2 -R", -NHC(=O)OR, -C(=0)NH-R, or -C 1 .-alkyl-C(=0)NH-R 11 , wherein the cycloC 3 - 12 alkyl is optionally unsaturated and wherein one carbon atom in the cycIoC3- 12 alkyl moiety may be replaced by an oxygen atom or an NR 12 -moiety; 197 WO 2005/082856 PCT/GB2005/000717 R 3 represents hydrogen, cyano, nitro, halogen, C 1 . 6 alkyl, CF 3 , heteroaryl, 2,3-dihydro-1 H-indenyl, hydroxy, C1.Ealkoxy, pyrrolidino, piperidino, or morpholino; 5 R 4 represents hydrogen, halogen, nitro, C 1 .-alkoxy, or hydroxy-C 2 -C alkoxy; R 5 and R 6 , which may be the same or different, each independently 10 represent hydrogen, hydroxy, C 1 . 6 alkyl; cycloC 3 .. 12 alkyl, C 2 - 6 alkenyl, C1. 6 alkoxy, C 1 ..alkoxyC 1 .ealkyl, C 1 . 6 alkylthio, C3. 6 alkenylthio, C1.6 alkylamino, di-C 1 . 6 alkylamino, cycloC 3 -1 2 alkylam ino, di-C 1 . 6 alkylaminoC 1 . 6 alkyl, aryl-C 1 .-alkylamino, aryl, aryl-C 1 . 6 alkyl, or aryl-C 2 - 6 alkenyl; 15 or one of R 5 and R 6 and one of R 7 and R 8 together represent -(CH 2 )n with n being 3, 4 or 5, while the remaining of R 5 and R3 as well as R 7 and R 8 are both hydrogen; 20 R 7 and R", which may be the same or different, each independently represent hydrogen, C 1 .ealkyl, cycIoC 3 - 1 2 alkyl, C 2 - 6 alkenyl, cycIoC 3 - 12 alkyl-C 1 . 6 alkyl, aryl, arylC 1 .Ealkyl, heteroaryl or heteroaryl-C 1 .. ealkyl; or R 7 and R 8 may together represent -(CH 2 )m- with m being 4, 5 or 6; 25 R 9 and R"), which may be the same or different, each independently represent hydrogen, C1. 6 alkyi, hydroxy, or C1. 6 alkoxy; R" represents hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, aryl, aryl-C1. 6 alkyl, 30 aryl-C 2 - 6 alkenyl, heteroaryl, heteroaryl-C 1 . 6 alkyl, C 1 . 6 alkylamino, di-C 1 . 6 alkylamino, cycloC 3 - 12 alkylamino, di-CI 6 alkylamino-C 1 . 6 alkyl, arylamino, aryl-C1.ealkylamino, aryl-C 2 -6alkenylamino, N-aryl-N-C1-6 alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, cycloC 3 . 1 2 alky, or 198 WO 2005/082856 PCT/GB2005/000717 cycloC 3 . 12 alkylC 1 . 6 alkyl, wherein the cycloC 3 12 alkyl is optionally unsaturated and wherein one carbon atom in the cycloC 3 .. 12 alkyl moiety may be replaced by an oxygen atom or an NR 12 moiety; 5 R 12 represents hydrogen, C 1 . 6 alkyl, aryl, heteroaryl, aryl-C 1 ..alkyl or heteroaryl-C 1 . 6 alkyl; it being understood that if one of R 5 and R 6 and one of R 7 and R" together represent -(CH 2 )n- with n being 3, 4 or 5, while the remaining of 10 R 5 and R 6 as well as R and R 8 are both hydrogen, then R 2 may also be halogen; and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof, 15 which is effective for alleviation of the condition.
  84. 100. The method of Claim 99, wherein the condition associated with glutamate induced excitation of the CNS is selected from AIDS-related 20 dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving B-amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), 25 multiple sclerosis (MS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, vascular and frontal lobe dementia, eye injuries, eye disorders, glaucoma, retinopathy, head and spinal cord injuries, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest, stroke, bypass 30 operations or transplants, seizures, convulsions, epliepsy, glioma and other tumours, inner ear insult, tinnitus, sound or drug-induced tinnitus, L-dopa induced dyskinesias, tardive dyskinesias, and Wilson's disease. 199 WO 2005/082856 PCT/GB2005/000717
  85. 101. The method of Claim 99, wherein the condition associated with glutamate induced excitation of the CNS is selected from addiction, nicotine addiction, alcohol addiction, opiate addiction, cocaine addiction, amphetamine addiction, obesity, amyotrophic lateral sclerosis (ALS), anxiety 5 and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, seizures, convulsions, epilepsy, dementia, Alzheimer's disease, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, Down syndrome, depression, depression resulting from Borna virus infection, bipolar manic-depressive 10 disorder, drug tolerance, drug tolerance to opioids, dyskinesias, L-Dopa induced dyskinesias, tardive dyskinesias, Huntington's disease, fragile-X syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, chronic pain, acute pain, Parkinson's disease, post traumatic stress disorder, schizophrenia, spasticity, tinnitus, 15 Tourette's syndrome, urinary incontinence, vomiting, and Wilson's disease.
  86. 102. A pharmaceutical composition comprising as active ingredient a compound of of Claim 1 together with together with one or more pharmaceutically acceptable excipients or vehicles. 20
  87. 103. Use of a compound of Formula IA R4 O R 5 R R 6 R IA 25 R2 N R 8 R 0 R 9 wherein R 2 represents C 1 . 6 alkyl, cycloC 3 -1 2 alkyl, cycloC 3 - 12 alkyl-C 1 6 alkyl, 30 C 2 . 6 alkenyl, C 2 .ealkynyl, aryl, biaryl, aryl-heteroaryl, heteroaryl heteroaryl, heteroaryl-aryl, aryl-C1. 6 alkyl, aryl-C 2 . 6 alkenyl, aryl C 2 . 6 alkynyl, heteroaryl, heteroaryl-C1. 6 alkyl, heteroary-C 2 - 6 alkenyl, heteroary-C 26 alkynyl, 2,3-dihydro-1 H-indenyl, C 1 . 6 alkoxy, hydroxy 200 WO 2005/082856 PCT/GB2005/000717 C 2 - 6 alkoxy, cycloC3- 1 2 alkoxy, cycIoC3-1 2 alkyl-C 1 . 6 alkoxy, aryloxy, aryl C 1 . 6 alkoxy, C 1 . 6 alkoxy-C 1 . 6 alkyl, C 1 .salkylthio, C4. 6 alkenylthio, cycloC 3 12 alkylthio, cycloC 3 -1 2 alkyl-C1. 6 alkylthio, cycloC 3 . 12 alkyl C 3 . 6 alkenylthio, C 1 .ealkoxy-C1. 6 alkylthio, C 1 .ealkoxy-C 3 .. salkenylthio, 5 aryl-C 1 _ 6 alkylthio, aryl-C 3 . 6 alkenylthio, heteroaryl-C 1 .. 6 alkylthio, C1.6 alkylsulfonyl, cycloC 3 . 12 alkyl-C 1 . 6 alkylsulfonyl, aryl-C 1 . 6 alkylsulfonyl, C 1 . 6 alkylamino, di-C 1 . 6 alkylamino, cycloC 3 1 2 alkylamino, C1. 6 alkoxy cycloC 3 . 12 alkylamino, cycloC 312 alkyl-C 1 . 6 alkylamino, di-C 1 . 6 alkylamino-C 1 . 6 alkyl, C 1 . 6 alkoxy-C 2 . 6 alkylamino, arylamino, aryl 10 C 1 . 6 alkylamino, N-cycloC3-1 2 alkyl-N-C 1 . 6 alkylamino, N-aryl-N C 1 . 6 alkylamino, N-arylC 1 . 6 alkyl-N-C 1 . 6 alkylamino, 2-indanylamino, 1,2,3,4-tetrahydroisoquinolin-2-yl, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C 1 .-alkylpiperazino, 4-arylpiperazino, 15 hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, heteroaryl-C 1 . 6 alkoxy, heteroarylamino, heteroaryl-C 1 . 6 alkylamino, -NHC(=O)-R", -NHSO 2 -R, -NHC(=0)OR, -C(=O)NH-R", or -C1. 6 alkyl-C(=O)NH-R", wherein the cycloC 3 - 12 alkyl is optionally unsaturated and wherein one carbon atom in the cycloC 3 . 2 alkyl 20 moiety may be replaced by an oxygen atom or an NR 12 -moiety; R 3 represents hydrogen, cyano, nitro, halogen, C 1 . 6 alkyl, CF 3 , heteroaryl, 2,3-dihydro-1 H-indenyl, hydroxy, C 1 . 6 alkoxy, pyrrolidino, piperidino, or morpholino; 25 R 4 represents hydrogen, halogen, nitro, C 1 .ealkoxy, or hydroxy-C 2 -E alkoxy; R 5 and R 6 which may be the same or different, each independently 30 represent hydrogen, hydroxy, C1.ealkyl; cycloC 3 . 2 alkyl, C 2 - 6 alkenyl, C 1 . 6 alkoxy, C1.ealkoxy-C1.6alkyl, C 1 .-alkylthio, C 3 -ealkenylthio, C 1 .e alkylamino, di-C 1 . 6 alkylamino, cycloC 3 . 12 alkylamino, di-C 1 . alkylamino C 1 . 6 alkyl, aryl-C 1 . 6 alkylamino, aryl, aryl-C 1 . 6 alkyl, or aryl-C 2 - 6 alkenyl; 201 WO 2005/082856 PCT/GB2005/000717 or one of R 5 and R 6 and one of R 7 and R 8 together represent -(CH 2 )n with n being 3, 4 or 5, while the remaining of R 5 and R 6 as well as R7 and R 8 are both hydrogen; 5 R 7 and R 8 , which may be the same or different, each independently represent hydrogen, C 1 . 6 alkyl, cycloC 3 . 12 alkyl, C 26 alkenyl, cycloC3- 2 alkyl-C 1 .salkyl, aryl, aryl-C 1 . 6 alkyl, heteroaryl, or heteroaryl-C 1 6 alkyl; or R7 and R 8 may together represent -(CH 2 )m- with m being 4, 5 or 6; 10 R 9 and R 10 , which may be the same or different, each independently represent hydrogen, C 1 .ealkyl, hydroxy, or C 1 . 6 alkoxy; R" represents hydrogen, CI 6 alkyl, C 2 - 6 alkenyl, aryl; aryl-C 1 .ealkyl, 15 aryl-C 2 - 6 alkenyl, heteroaryl, heteroary-C 1 . 6 alkyl, C 1 .salkylamino, di-C 1 . 6 alkylamino, cycloC 3 - 12 alkylamino, di-C 1 . 6 alkylamino-C 1 . 6 alkyl, arylamino, aryl-CI. 6 alkylamino, aryl-C 2 -Salkenylamino, N-aryl-N-C 1 .6 alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-y, cycloC 3 . 12 alkyl, or 20 cycloC 3 - 12 lkylC 1 . 6 alkyl, wherein the cycloC 3 . 12 akyl is optionally unsaturated and wherein one carbon atom in the cycloC 3 - 12 alkyl moiety may be replaced by an oxygen atom or an NR 2 moiety; R 12 represents hydrogen, C 1 . 6 alkyl, aryl, heteroaryl, aryl-C 1 .Ealkyl or 25 heteroary-C 1 .salkyl; it being understood that if one of R 5 and R 6 and one of R 7 and R8 together represent -(CH 2 )n- with n being 3, 4 or 5, while the remaining of R 5 and R5 as well as R 7 and R6 are both hydrogen, then R 2 may 30 also be halogen; and optical isomers, polymorphs and pharmaceutically-acceptable acid and base addition salts, hydrates, and solvates thereof, 202 WO 2005/082856 PCT/GB2005/000717 for the manufacturing of a medicament for treating a living animal body, including a human, afflicted with a condition associated with glutamate induced excitation of the CNS. 5 104. Use of Claim 103 wherein the condition associated with glutamate induced excitation of the CNS is selected from AIDS-related dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving f3-amyloid and/or tauopathy 10 such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, vascular and frontal lobe dementia, eye injuries, eye disorders (e.g. glaucoma, retinopathy), head and spinal cord 15 injuries, trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), seizures, convulsions, epliepsy, glioma and other tumours, inner ear insult (e.g. in tinnitus, sound or drug-induced), L-dopa-induced and tardive dyskinesias, Wilson's disease. 20
  88. 105. Use of Claim 103, wherein the condition associated with glutamate induced excitation of the CNS is selected from addiction (nicotine, alcohol, opiate, cocaine, amphetamine obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention deficit hyperactivity 25 disorder (ADHD), restless leg syndrome and hyperactive children, autism, seizures, convulsions, epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections, Down syndrome), depression (including that resulting from Borna virus infection) and bipolar manic-depressive disorder, drug tolerance e.g. to opioids, dyskinesia (e.g. L 30 Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain (chronic and acute), Parkinson's disease, post traumatic stress disorder, schizophrenia, spasticity, tinnitus, Tourette's syndrome, urinary incontinence and vomiting, Wilson's disease. 203
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